bluuebunny/crossref_metadata_2025 huggingface dataset:
Radar Reflectivity and Altitude Distributions of Lightning as a Function of IC, CG, and HY Flashes: Implications for LNOx Production
Authors: Mecikalski Retha M. , Carey Lawrence D.
Published: November 2018

Two dimensional (2‐D) histogram distributions of lightning flashes relative to radar reflectivity and altitude were created using a total of 41,180 intercloud/intracloud (IC) flashes, 3,326 cloud‐to‐ground (CG) flashes, and 4,349 hybrid (HY) flashes that originated in multicells; 111,479 IC flashes, 8,588 CG flashes, and 11,699 HY flashes that originated in mesoscale convective systems; and 91,283 IC flashes, 3,023 CG flashes, and 7,872 HY flashes that originated in supercells that occurred over northern Alabama and southern Tennessee. It was shown that although CG flashes initiate and propagate at the same altitude irrespective of storm type, IC flashes could have differences of up to 10 °C, while for HY flashes these differences increased to up to 20 °C relative to storm type. Further, IC, CG, and HY flashes propagated in lower reflectivities than where they initiated, while CG flashes initiated and propagated within higher reflectivities than IC and HY flashes. HY flashes were also twice as large as IC flashes and ~40% larger than CG flashes, and flashes that originated in mesoscale convective systems had larger overall sizes as compared to multicells and supercells. When comparing the new 2‐D histogram distributions to the legacy distributions used for the calculation of lightning‐produced nitrogen oxides (LNOx), it was shown that the new distributions perform much better, with higher Pearson product moment correlation coefficient values and much lower root‐mean‐square errors. These new distributions are thus more appropriate to use when modeling LNOx and will lead to more accurate LNOx estimations than using the legacy distributions.
ClNO2 Yields From Aircraft Measurements During the 2015 WINTER Campaign and Critical Evaluation of the Current Parameterization
Authors: McDuffie Erin E. , Fibiger Dorothy L. , Dubé William P. , Lopez Hilfiker Felipe , Lee Ben H. , Jaeglé Lyatt , Guo Hongyu , Weber Rodney J. , Reeves J. Michael , Weinheimer Andrew J. , Schroder Jason C. , Campuzano‐Jost Pedro , Jimenez Jose L. , Dibb Jack E. , Veres Patrick , Ebben Carlena , Sparks Tamara L. , Wooldridge Paul J. , Cohen Ronald C. , Campos Teresa , Hall Samuel R. , Ullmann Kirk , Roberts James M. , Thornton Joel A. , Brown Steven S.
Published: November 2018

Nitryl chloride (ClNO2) plays an important role in the budget and distribution of tropospheric oxidants, halogens, and reactive nitrogen species. ClNO2 is formed from the heterogeneous uptake and reaction of dinitrogen pentoxide (N2O5) on chloride‐containing aerosol, with a production yield, ϕ(ClNO2), defined as the moles of ClNO2 produced relative to N2O5 lost. The ϕ(ClNO2) has been increasingly incorporated into 3‐D chemical models where it is parameterized based on laboratory‐derived kinetics and currently accepted aqueous‐phase formation mechanism. This parameterization models ϕ(ClNO2) as a function of the aerosol chloride to water molar ratio. Box model simulations of night flights during the 2015 Wintertime INvestigation of Transport, Emissions, and Reactivity (WINTER) aircraft campaign derived 3,425 individual ϕ(ClNO2) values with a median of 0.138 and range of 0.003 to 1. Comparison of the box model median to those predicted by two other field‐based ϕ(ClNO2) derivation methods agreed within a factor of 1.3, within the uncertainties of each method. In contrast, the box model median was 75–84% lower than predictions from the laboratory‐based parameterization (i.e., [parameterization − box model]/parameterization). An evaluation of factors influencing this difference reveals a positive dependence of ϕ(ClNO2) on aerosol water, opposite to the currently parameterized trend. Additional factors may include aqueous‐phase competition reactions for the nitronium ion intermediate and/or direct ClNO2 loss mechanisms. Further laboratory studies of ClNO2 formation and the impacts of aerosol water, sulfate, organics, and ClNO2 aqueous‐phase reactions are required to elucidate and quantify these processes on ambient aerosol, critical for the development of a robust ϕ(ClNO2) parameterization.
Early Pleistocene Obliquity‐Scale pCO2 Variability at ~1.5 Million Years Ago
Authors: Dyez Kelsey A. , Hönisch Bärbel , Schmidt Gavin A.
Published: November 2018

In the early Pleistocene, global temperature cycles predominantly varied with ~41‐kyr (obliquity‐scale) periodicity. Atmospheric greenhouse gas concentrations likely played a role in these climate cycles; marine sediments provide an indirect geochemical means to estimate early Pleistocene CO2. Here we present a boron isotope‐based record of continuous high‐resolution surface ocean pH and inferred atmospheric CO2 changes. Our results show that, within a window of time in the early Pleistocene (1.38–1.54 Ma), pCO2 varied with obliquity, confirming that, analogous to late Pleistocene conditions, the carbon cycle and climate covaried at ~1.5 Ma. Pairing the reconstructed early Pleistocene pCO2 amplitude (92 ± 13 μatm) with a comparably smaller global surface temperature glacial/interglacial amplitude (3.0 ± 0.5 K) yields a surface temperature change to CO2 radiative forcing ratio of S[CO2]~0.75 (±0.5) °C−1·W−1·m−2, as compared to the late Pleistocene S[CO2] value of ~1.75 (±0.6) °C−1·W−1·m−2. This direct comparison of pCO2 and temperature implicitly incorporates the large ice sheet forcing as an internal feedback and is not directly applicable to future warming. We evaluate this result with a simple climate model and show that the presumably thinner, though extensive, northern hemisphere ice sheets would increase surface temperature sensitivity to radiative forcing. Thus, the mechanism to dampen actual temperature variability in the early Pleistocene more likely lies with Southern Ocean circulation dynamics or antiphase hemispheric forcing. We also compile this new carbon dioxide record with published Plio‐Pleistocene δ11B records using consistent boundary conditions and explore potential reasons for the discrepancy between Pliocene pCO2 based on different planktic foraminifera.
Using Lightning as a HF Signal Source to Produce Ionograms
Authors: Obenberger K. S. , Dowell J. D. , Malins J. , Parris R. T. , Pedersen T. R. , Taylor G. B.
Published: November 2018

Modern techniques for specifying the ionosphere include the use of ionosondes, which both transmit and receive sweep soundings in the high‐frequency (HF) band. We replicate this process by observing the broad band emission from lightning using the Long Wavelength Array, Sevilleta, radio telescope. We use this station to observe the powerful broadband radio bursts from the breakdown of air that occurs during lightning flashes. For nearby lightning we observe both the direct line of sight and the delayed ionospheric reflection. By correlating the amplitude time series from the direct line of sight to that of the ionospheric reflection, we can accurately measure the group delay as a function of frequency. By separating into right‐hand circular and left‐hand circular, we can derive both the O mode and X mode ionograms. This novel technique allows for accurate ionograms to be made even in restricted frequency bands and provides a means to probe density profiles at multiple locations of the ionosphere on short time scales with a single receiver station.
The DST Group High‐Fidelity, Multichannel Oblique Incidence Ionosonde
Authors: Ayliffe Jim K. , Durbridge Lyndon J. , Frazer Gordon J. , Gardiner‐Garden Robert S. , Heitmann Andrew J. , Praschifka Justin , Quinn Adrian D. , Scarman Gavin C. , Turley Mike D. E.
Published: November 2018

Defence Science and Technology Group has developed a complete oblique incidence ionosonde system to enhance ionospheric monitoring capabilities in support of the Jindalee Operational Radar Network. The Digital Oblique Receiving System, and its counterpart, the Digital Oblique Transmitting System, feature a direct‐digital, multichannel chirp‐sounder design that allows flexible collection of high‐resolution ionograms across many simultaneous paths, without compromising dynamic range. This paper outlines the hardware and software components of the Digital Oblique Receiving System/Digital Oblique Transmitting System, including the onboard signal processing that removes radio frequency interference and fits a parameterized electron density profile to the ionogram. Additional control and data management tools that have enabled the system to be effectively transitioned into routine operations are also described. The typical performance is illustrated through a selection of sample ionograms, highlighting the applications of Digital Oblique Receiving System/Digital Oblique Transmitting System to a wide variety of ionospheric studies, including those requiring Doppler and angle‐of‐arrival observations.
Combining Ground‐Penetrating Radar With Terrestrial LiDAR Scanning to Estimate the Spatial Distribution of Liquid Water Content in Seasonal Snowpacks
Authors: Webb R. W. , Jennings K. S. , Fend M. , Molotch N. P.
Published: November 2018

Many communities and ecosystems around the world rely on mountain snowpacks to provide valuable water resources. An important consideration for water resources planning is runoff timing, which can be strongly influenced by the physical process of water storage within and release from seasonal snowpacks. The aim of this study is to present a novel method that combines light detection and ranging with ground‐penetrating radar to nondestructively estimate the spatial distribution of bulk liquid water content in a seasonal snowpack during spring snowmelt. We develop these methods in a manner to be applicable within a short time window, making it possible to spatially observe rapid changes that occur to this property at subdaily timescales. We applied these methods at two experimental plots in Colorado, showing the high variability of liquid water content in snow. Volumetric liquid water contents ranged from near zero to 19%vol within the scale of meters. We also show rapid changes in bulk liquid water content of up to 5%vol that occur over subdaily timescales. The presented methods have an average uncertainty in bulk liquid water content of 1.5%vol, making them applicable for future studies to estimate the complex spatio‐temporal dynamics of liquid water in snow.
Modeling Macroroughness Contribution to Fish Habitat Suitability Curves
Authors: Niayifar Amin , Oldroyd Holly J. , Lane Stuart N. , Perona Paolo
Published: November 2018

Improved water management strategies necessitate a solid understanding of environmental impacts associated with various flow release policies. Habitat suitability models use hydrodynamic simulations to generate weighted usable area curves, which are useful in characterizing the ecological suitability of flow release rules. However, these models are not conveniently run to resolve the hydrodynamics at the smaller scales associated with macroroughness elements (e.g., individual stones), which produce wakes that contribute significantly to habitat suitability by serving as shelter zones where fishes can rest and feed. In this study, we propose a robust environmental indicator that considers the habitat generated by the wakes downstream of stones and can thus be used to assess the environmental efficiency of flow release rules for impounded streams. We develop an analytical solution to approximate the wake areas behind macroroughness elements, and the statistical distribution of wake areas is then found using the derived distribution approach. To illustrate the concept, we apply our theory to four exemplary river streams with dispersed stones having different statistical diameter size distributions, some of which allow for an analytical expression of the weighted usable area. We additionally investigate the impact of spatiotemporal changes in stone size distributions on the usable area and the consequent threshold flows. Finally, we include the proposed environmental indicator to solve a multiobjective reservoir optimization problem. This exemplifies its practical use and allows stakeholders to find the most favorable operational rules depending on the macroroughness characteristics of the impounded stream.
Relating Degradation of Pharmaceutical Active Ingredients in a Stream Network to Degradation in Water‐Sediment Simulation Tests
Authors: Honti Mark , Bischoff Fabian , Moser Andreas , Stamm Christian , Baranya Sándor , Fenner Kathrin
Published: November 2018

Many pharmaceuticals inevitably end up in surface waters, exerting unwanted biological activity in nontarget organisms. This effect is confined by the compound's environmental persistence. Regulatory laboratory simulation tests are used in persistence assessment and exposure modeling. While doubt has been expressed about the usefulness of laboratory‐derived persistence indicators under field conditions, these remain the only inputs for chemical fate models due to difficulties of measuring persistence in situ, especially at large scales. To improve understanding about relationships between laboratory experiments and the environmental fate in streams, we developed a mathematical model of biodegradation in stream networks and combined it with in‐stream monitoring data to (i) test if persistence could be evaluated from field data, (ii) check if persistence extracted from laboratory tests applied in the field, and (iii) locate hot spots of biodegradation in a large river basin. The model describes partitioning, and particle settling and resuspension, and is structurally compatible with those applied for evaluating laboratory simulation tests. Application to the Rhine river basin suggests that biotransformation rate constants extracted from laboratory tests underestimate those in the field, yet the percentage of biotransformation in the Rhine basin is less than in the laboratory tests due effective biotransformation being limited to small‐ and medium‐sized streams. In conclusion, our data show that biotransformation rates can accurately be predicted if (i) monitoring is performed across a wide range in stream order and (ii) precise estimates for consumption and removal rates at wastewater treatment plants are known.
Quantifying the changes in genetic diversity within sequence-discrete bacterial populations across a spatial and temporal riverine gradient
Authors: Meziti Alexandra , Tsementzi Despina , Rodriguez-R Luis M , Hatt Janet K , Karayanni Hera , Kormas Konstantinos A , Konstantinidis Konstantinos T
Published: November 2018

Recent diversity studies have revealed that microbial communities of natural environments are dominated by species-like, sequence-discrete populations. However, how stable the sequence and gene-content diversity are within these populations and especially in highly dynamic lotic habitats remain unclear. Here we quantified the dynamics of intra-population diversity in samples spanning two years and five sites in the Kalamas River (Northwest Greece). A significant positive correlation was observed between higher intra-population sequence diversity and longer persistence over time, revealing that more diverse populations tended to represent more autochthonous (vs. allochthonous) community members. Assessment of intra-population gene-content changes caused by strain replacement or gene loss over time revealed different profiles with the majority of populations exhibiting gene-content changes close to 10% of the total genes, while one population exhibited ~21% change. The variable genes were enriched in hypothetical proteins and mobile elements, and thus, were probably functionally neutral or attributable to phage predation. A few notable exceptions to this pattern were also noted such as phototrophy-related proteins in summer vs. winter populations. Taken together, these results revealed that some freshwater genomes are remarkably dynamic, even across short time and spatial scales, and have implications for the bacterial species concept and microbial source tracking.
Predicting the naturalistic course of depression from a wide range of clinical, psychological, and biological data: a machine learning approach
Authors: Dinga Richard , Marquand Andre F. , Veltman Dick J. , Beekman Aartjan T. F. , Schoevers Robert A. , van Hemert Albert M. , Penninx Brenda W. J. H. , Schmaal Lianne
Published: November 2018

Many variables have been linked to different course trajectories of depression. These findings, however, are based on group comparisons with unknown translational value. This study evaluated the prognostic value of a wide range of clinical, psychological, and biological characteristics for predicting the course of depression and aimed to identify the best set of predictors. Eight hundred four unipolar depressed patients (major depressive disorder or dysthymia) patients were assessed on a set involving 81 demographic, clinical, psychological, and biological measures and were clinically followed-up for 2 years. Subjects were grouped according to (i) the presence of a depression diagnosis at 2-year follow-up (yes n = 397, no n = 407), and (ii) three disease course trajectory groups (rapid remission, n = 356, gradual improvement n = 273, and chronic n = 175) identified by a latent class growth analysis. A penalized logistic regression, followed by tight control over type I error, was used to predict depression course and to evaluate the prognostic value of individual variables. Based on the inventory of depressive symptomatology (IDS), we could predict a rapid remission course of depression with an AUROC of 0.69 and 62% accuracy, and the presence of an MDD diagnosis at follow-up with an AUROC of 0.66 and 66% accuracy. Other clinical, psychological, or biological variables did not significantly improve the prediction. Among the large set of variables considered, only the IDS provided predictive value for course prediction on an individual level, although this analysis represents only one possible methodological approach. However, accuracy of course prediction was moderate at best and further improvement is required for these findings to be clinically useful.
Deferred autologous stem cell transplantation in systemic AL amyloidosis
Authors: Manwani Richa , Hegenbart Ute , Mahmood Shameem , Sachchithanantham Sajitha , Kyriakou Charalampia , Yong Kwee , Popat Rakesh , Rabin Neil , Whelan Carol , Dittrich Tobias , Kimmich Christoph , Hawkins Philip , Schönland Stefan , Wechalekar Ashutosh
Published: November 2018

High-dose melphalan with autologous stem cell transplantation (ASCT) can induce durable haematological and organ responses in systemic AL amyloidosis (AL). Stringent selection criteria have improved safety of ASCT in AL but most patients are transplant-ineligible. We report our experience of deferred ASCT in AL patients who were transplant-ineligible at presentation but had improvements in organ function after induction chemotherapy, enabling them to undergo ASCT. Twenty-two AL patients underwent deferred ASCT from 2011 to 2017. All had serial organ function and clonal response assessment. Organ involvement and responses were defined by amyloidosis consensus criteria. All patients were transplant-ineligible at presentation, predominantly due to advanced cardiac involvement. All received bortezomib-based therapy, with 100% haematologic response (86% complete response (CR)/very good partial response (VGPR)), enabling reversal of ASCT exclusion criteria. Patients underwent deferred ASCT for haematologic progression (45%) or consolidation (55%). There was no transplant-related mortality. Haematologic responses post-ASCT: CR 50%, VGPR 27%, PR 18%, non-response 5%. In all, 85.7% achieved cardiac responses. Median overall survival (OS) was not reached. Median progression-free survival (PFS) was 54 months. This selected cohort achieved excellent haematologic responses, organ responses, PFS and OS with deferred ASCT. If larger studies confirm these findings, this may widen the applicability of ASCT in AL.
Fossilization transforms vertebrate hard tissue proteins into N-heterocyclic polymers
Authors: Wiemann Jasmina , Fabbri Matteo , Yang Tzu-Ruei , Stein Koen , Sander P. Martin , Norell Mark A. , Briggs Derek E. G.
Published: November 2018

Vertebrate hard tissues consist of mineral crystallites within a proteinaceous scaffold that normally degrades post-mortem. Here we show, however, that decalcification of Mesozoic hard tissues preserved in oxidative settings releases brownish stained extracellular matrix, cells, blood vessels, and nerve projections. Raman Microspectroscopy shows that these fossil soft tissues are a product of diagenetic transformation to Advanced Glycoxidation and Lipoxidation End Products, a class of N-heterocyclic polymers generated via oxidative crosslinking of proteinaceous scaffolds. Hard tissues in reducing environments, in contrast, lack soft tissue preservation. Comparison of fossil soft tissues with modern and experimentally matured samples reveals how proteinaceous tissues undergo diagenesis and explains biases in their preservation in the rock record. This provides a target, focused on oxidative depositional environments, for finding cellular-to-subcellular soft tissue morphology in fossils and validates its use in phylogenetic and other evolutionary studies.
Crystal structures of human ETB receptor provide mechanistic insight into receptor activation and partial activation
Authors: Shihoya Wataru , Izume Tamaki , Inoue Asuka , Yamashita Keitaro , Kadji Francois Marie Ngako , Hirata Kunio , Aoki Junken , Nishizawa Tomohiro , Nureki Osamu
Published: November 2018

Endothelin receptors (ETA and ETB) are class A GPCRs activated by vasoactive peptide endothelins, and are involved in blood pressure regulation. ETB-selective signalling induces vasorelaxation, and thus selective ETB agonists are expected to be utilized for improved anti-tumour drug delivery and neuroprotection. Here, we report the crystal structures of human ETB receptor in complex with ETB-selective agonist, endothelin-3 and an ETB-selective endothelin analogue IRL1620. The structure of the endothelin-3-bound receptor reveals that the disruption of water-mediated interactions between W6.48 and D2.50 is critical for receptor activation, while these hydrogen-bonding interactions are partially preserved in the IRL1620-bound structure. Consistently, functional analysis reveals the partial agonistic effect of IRL1620. The current findings clarify the detailed molecular mechanism for the coupling between the orthosteric pocket and the G-protein binding, and the partial agonistic effect of IRL1620, thus paving the way for the design of improved agonistic drugs targeting ETB.
Crystallographic and spectroscopic assignment of the proton transfer pathway in [FeFe]-hydrogenases
Authors: Duan Jifu , Senger Moritz , Esselborn Julian , Engelbrecht Vera , Wittkamp Florian , Apfel Ulf-Peter , Hofmann Eckhard , Stripp Sven T. , Happe Thomas , Winkler Martin
Published: November 2018

The unmatched catalytic turnover rates of [FeFe]-hydrogenases require an exceptionally efficient proton-transfer (PT) pathway to shuttle protons as substrates or products between bulk water and catalytic center. For clostridial [FeFe]-hydrogenase CpI such a pathway has been proposed and analyzed, but mainly on a theoretical basis. Here, eleven enzyme variants of two different [FeFe]-hydrogenases (CpI and HydA1) with substitutions in the presumptive PT-pathway are examined kinetically, spectroscopically, and crystallographically to provide solid experimental proof for its role in hydrogen-turnover. Targeting key residues of the PT-pathway by site directed mutagenesis significantly alters the pH-activity profile of these variants and in presence of H2 their cofactor is trapped in an intermediate state indicative of precluded proton-transfer. Furthermore, crystal structures coherently explain the individual levels of residual activity, demonstrating e.g. how trapped H2O molecules rescue the interrupted PT-pathway. These features provide conclusive evidence that the targeted positions are indeed vital for catalytic proton-transfer.
Evidence of depolarization and ellipticity of high harmonics driven by ultrashort bichromatic circularly polarized fields
Authors: Barreau Lou , Veyrinas Kévin , Gruson Vincent , Weber Sébastien J. , Auguste Thierry , Hergott Jean-François , Lepetit Fabien , Carré Bertrand , Houver Jean-Christophe , Dowek Danielle , Salières Pascal
Published: November 2018

High harmonics generated by counter-rotating laser fields at the fundamental and second harmonic frequencies have raised important interest as a table-top source of circularly polarized ultrashort extreme-ultraviolet light. However, this emission has not yet been fully characterized: in particular it was assumed to be fully polarized, leading to an uncertainty on the effective harmonic ellipticity. Here we show, through simulations, that ultrashort driving fields and ultrafast medium ionization lead to a breaking of the dynamical symmetry of the interaction, and consequently to deviations from perfectly circular and fully polarized harmonics, already at the single-atom level. We perform the complete experimental characterization of the polarization state of high harmonics generated along that scheme, giving direct access to the ellipticity absolute value and sign, as well as the degree of polarization of individual harmonic orders. This study allows defining optimal generation conditions of fully circularly polarized harmonics for advanced studies of ultrafast dichroisms.
Active intermixing of indirect and direct neurons builds the striatal mosaic
Authors: Tinterri Andrea , Menardy Fabien , Diana Marco A. , Lokmane Ludmilla , Keita Maryama , Coulpier Fanny , Lemoine Sophie , Mailhes Caroline , Mathieu Benjamin , Merchan-Sala Paloma , Campbell Kenneth , Gyory Ildiko , Grosschedl Rudolf , Popa Daniela , Garel Sonia
Published: November 2018

The striatum controls behaviors via the activity of direct and indirect pathway projection neurons (dSPN and iSPN) that are intermingled in all compartments. While such cellular mosaic ensures the balanced activity of the two pathways, its developmental origin and pattern remains largely unknown. Here, we show that both SPN populations are specified embryonically and intermix progressively through multidirectional iSPN migration. Using conditional mutant mice, we found that inactivation of the dSPN-specific transcription factor Ebf1 impairs selective dSPN properties, including axon pathfinding, while molecular and functional features of iSPN were preserved. Ebf1 mutation disrupted iSPN/dSPN intermixing, resulting in an uneven distribution. Such architectural defect was selective of the matrix compartment, highlighting that intermixing is a parallel process to compartment formation. Our study reveals while iSPN/dSPN specification is largely independent, their intermingling emerges from an active migration of iSPN, thereby providing a novel framework for the building of striatal architecture.
Discovery of rare cells from voluminous single cell expression data
Authors: Jindal Aashi , Gupta Prashant , Jayadeva  , Sengupta Debarka
Published: November 2018

Single cell messenger RNA sequencing (scRNA-seq) provides a window into transcriptional landscapes in complex tissues. The recent introduction of droplet based transcriptomics platforms has enabled the parallel screening of thousands of cells. Large-scale single cell transcriptomics is advantageous as it promises the discovery of a number of rare cell sub-populations. Existing algorithms to find rare cells scale unbearably slowly or terminate, as the sample size grows to the order of tens of thousands. We propose Finder of Rare Entities (FiRE), an algorithm that, in a matter of seconds, assigns a rareness score to every individual expression profile under study. We demonstrate how FiRE scores can help bioinformaticians focus the downstream analyses only on a fraction of expression profiles within ultra-large scRNA-seq data. When applied to a large scRNA-seq dataset of mouse brain cells, FiRE recovered a novel sub-type of the pars tuberalis lineage.
Spontaneous formation of nanoparticles on electrospun nanofibres
Authors: Radacsi Norbert , Campos Fernando Diaz , Chisholm Calum R. I. , Giapis Konstantinos P.
Published: November 2018

We report the spontaneous formation of nanoparticles on smooth nanofibres in a single-step electrospinning process, as an inexpensive and scalable method for producing high-surface-area composites. Layers of nanofibres, containing the proton conducting electrolyte, caesium dihydrogen phosphate, are deposited uniformly over large area substrates from clear solutions of the electrolyte mixed with polymers. Under certain conditions, the normally smooth nanofibres develop caesium dihydrogen phosphate nanoparticles in large numbers on their external surface. The nanoparticles appear to originate from the electrolyte within the fibres, which is transported to the outer surface after the fibres are deposited, as evidenced by cross-sectional imaging of the electrospun fibres. The presence of nanoparticles on the fibre surface yields composites with increased surface area of exposed electrolyte, which ultimately enhances electrocatalytic performance. Indeed, solid acid fuel cells fabricated with electrodes from processed nanofibre-nanoparticle composites, produced higher cell voltage as compared to fuel cells fabricated with state-of-the-art electrodes.
Design and 22-step synthesis of highly potent D-ring modified and linker-equipped analogs of spongistatin 1
Authors: Suen Linda M. , Tekle-Smith Makeda A. , Williamson Kevin S. , Infantine Joshua R. , Reznik Samuel K. , Tanis Paul S. , Casselman Tyler D. , Sackett Dan L. , Leighton James L.
Published: November 2018

Spongistatin 1 is among the most potent anti-proliferative agents ever discovered rendering it an attractive candidate for development as a payload for antibody–drug conjugates and other targeted delivery approaches. Unfortunately, it is unavailable from natural sources and its size and complex stereostructure render chemical synthesis highly time- and resource-intensive. As a result, the design and synthesis of more acid-stable and linker functional group-equipped analogs that retain the low picomolar potency of the parent natural product requires more efficient and step-economical synthetic access. Using uniquely enabling direct complex fragment coupling crotyl- and alkallylsilylation reactions, we report a 22-step synthesis of a rationally designed D-ring modified analog of spongistatin 1 that is characterized by GI50 values in the low picomolar range, and a proof-of-concept result that the C(15) acetate may be replaced with linker functional group-bearing esters with only minimal reductions in potency.
Thermochronological insights into reactivation of a continental shear zone in response to Equatorial Atlantic rifting (northern Ghana)
Authors: Fernie Nicholas , Glorie Stijn , Jessell Mark W. , Collins Alan S.
Published: November 2018

West Africa was subjected to deformation and exhumation in response to Gondwana break-up. The timing and extent of these events are recorded in the thermal history of the margin. This study reports new apatite fission track (AFT) data from Palaeoproterozoic basement along the primary NE-SW structural trend of the Bole-Nangodi shear zone in northwestern Ghana. The results display bimodality in AFT age (populations of ~210-180 Ma and ~115-105 Ma) and length distributions (populations of 12.2 ± 1.6 and 13.1 ± 1.4 µm), supported by differences in apatite chemistry (U concentrations). The bimodal AFT results and associated QTQt thermal history models provide evidence for multiple cooling phases. Late Triassic – Early Jurassic cooling is interpreted to be related with thermal relaxation after the emplacement of the Central Atlantic Magmatic Province (CAMP). Early to middle Cretaceous cooling is thought to be associated with exhumation during the Cretaceous onset of rifting between West Africa and Brazil. Late Cretaceous – Cenozoic cooling can be related with exhumation of the Ivory Coast – Ghana margin and NNW-SSE shortening through western Africa. Furthermore, our data record differential exhumation of the crust with respect to the Bole-Nangodi shear zone, preserving older (CAMP) cooling ages to the south and younger (rifting) cooling ages to the north of the shear zone, respectively. This suggests that the Palaeoproterozoic BN shear zone was reactivated during the Cretaceous as a result of deformation in the Equatorial Atlantic region of Africa.
Amyloid precursor protein-fragments-containing inclusions in cardiomyocytes with basophilic degeneration and its association with cerebral amyloid angiopathy and myocardial fibrosis
Authors: Krämer Lara Maria , Brettschneider Johannes , Lennerz Jochen K. , Walcher Daniel , Fang Lubin , Rosenbohm Angela , Balakrishnan Karthikeyan , Benckendorff Julian , Möller Peter , Just Steffen , Willem Michael , Ludolph Albert C. , Thal Dietmar Rudolf
Published: November 2018

Cardiomyopathies with intracellular inclusions are a distinct subset of cardiomyopathies whereas basophilic degeneration (BD) of the heart describes inclusions in cardiomyocytes of the aging heart, which have not yet been related to a specific disease condition or to a distinct type of protein inclusion. To address the question whether BD represents a specific pathological feature and whether it is linked to a distinct disease condition we studied 62 autopsy cases. BD inclusions exhibited an immunohistochemical staining pattern related to glycosylated, δ- or η-secretase-derived N-terminal cleavage products of the amyloid precursor protein (sAPPδ/η) or shorter fragments of sAPPη. BD aggregates were found in the myocardium of both ventricles and atria with highest amounts in the atria and lowest in the interventricular septum. The frequency of BD-lesions correlated with age, degree of myocardial fibrosis in individuals with arterial hypertension, and the severity of cerebral amyloid angiopathy (CAA). The intracytoplasmic deposition of N-terminal sAPPδ/η fragments in BD indicates a specific inclusion body pathology related to APP metabolism. The correlation with the severity of CAA, which is related to the APP-derived amyloid β-protein, supports this point of view and suggests a possible link between myocardial and cerebrovascular APP-related lesions.
Functional analysis of potential cleavage sites in the MERS-coronavirus spike protein
Authors: Kleine-Weber Hannah , Elzayat Mahmoud Tarek , Hoffmann Markus , Pöhlmann Stefan
Published: November 2018

The Middle East respiratory syndrome-related coronavirus (MERS-CoV) can cause severe disease and has pandemic potential. Therefore, development of antiviral strategies is an important task. The activation of the viral spike protein (S) by host cell proteases is essential for viral infectivity and the responsible enzymes are potential therapeutic targets. The cellular proteases furin, cathepsin L and TMPRSS2 can activate MERS-S and may cleave the S protein at two distinct sites, termed S1/S2 and S2′. Moreover, a potential cathepsin L cleavage site in MERS-S has been reported. However, the relative importance of these sites for MERS-S activation is incompletely understood. Here, we used mutagenic analysis and MERS-S-bearing vectors to study the contribution of specific cleavage sites to S protein-driven entry. We found that an intact S1/S2 site was only required for efficient entry into cells expressing endogenous TMPRSS2. In keeping with a previous study, pre-cleavage at the S1/S2 motif (RSVR) was important although not essential for subsequent MERS-S activation by TMPRSS2, and indirect evidence was obtained that this motif is processed by a protease depending on an intact RXXR motif, most likely furin. In contrast, the S2′ site (RSAR) was required for robust viral entry into all cell lines tested and the integrity of one of the two arginines was sufficient for efficient entry. These findings suggest that cleavage at S2′ is carried out by proteases recognizing a single arginine, most likely TMPRSS2 and cathepsin L. Finally, mutation of the proposed cathepsin L site did not impact viral entry and double mutation of S1/S2 and S2′ site was compatible with cathepsin L- but not TMPRSS2-dependent host cell entry, indicating that cathepsin L can process the S protein at auxiliary sites. Collectively, our results indicate a rigid sequence requirement for S protein activation by TMPRSS2 but not cathepsin L.
Structure analysis and antiviral activity of CW-33 analogues against Japanese encephalitis virus
Authors: Lien Jin-Cherng , Wang Ching-Ying , Lai Hsueh–Chou , Lu Chien-Yi , Lin Yu-Fong , Gao Ging-Yan , Chen Kuan-Chung , Huang An-Cheng , Huang Su-Hua , Lin Cheng-Wen
Published: November 2018

Japanese encephalitis virus (JEV) is a member of neurotropic flaviviruses transmitted by mosquito bites, causing severe central nervous system disorders. Current JEV genotype III vaccines have a low protection against genotype I isolates in the risk zone. The lead compound CW-33, ethyl 2-(3′,5′-dimethylanilino)-4-oxo-4,5-dihydrofuran-3-carboxylate, demonstrates the antiviral activity against JEV with an IC50 values of 38.5 μM for virus yield reduction (Int J Mol Sci 2016,17: E1386). This study synthesized fourteen CW-33 analogues containing a fluoro atom or one methoxy group at the C-2, C-3, or C-4 of anilino ring, and then evaluated for their antiviral activity and mechanism. Among 6 amalogues, CW-33A (ethyl 2-(2-fluoroanilino)-4-oxo- 4,5-dihydrofuran-3-carboxylate), and CW-33D (ethyl 2-(3-methoxyanilino)-4-oxo- 4,5-dihydrofuran-3-carboxylate exhibited antiviral potentials in viral cytopathic effect (CPE) inhibition. CW-33A significantly suppressed the viral protein expression, genome synthesis and intracellular JEV particle production, showing a higher inhibitory effect on JEV yield than CW-33 and CW-33D. The study demonstrated that a mono-fluoro substitution on at the C-2 anilino ring of CW-33 improved the antiviral activity JEV, revealing the structure-activity relationship for developing novel agents against JEV infection.
The two phases of the Cambrian Explosion
Authors: Zhuravlev Andrey Yu. , Wood Rachel A.
Published: November 2018

The dynamics of how metazoan phyla appeared and evolved – known as the Cambrian Explosion – remains elusive. We present a quantitative analysis of the temporal distribution (based on occurrence data of fossil species sampled in each time interval) of lophotrochozoan skeletal species (n = 430) from the terminal Ediacaran to Cambrian Stage 5 (~545 – ~505 Million years ago (Ma)) of the Siberian Platform, Russia. We use morphological traits to distinguish between stem and crown groups. Possible skeletal stem group lophophorates, brachiopods, and molluscs (n = 354) appear in the terminal Ediacaran (~542 Ma) and diversify during the early Cambrian Terreneuvian and again in Stage 2, but were devastated during the early Cambrian Stage 4 Sinsk extinction event (~513 Ma) never to recover previous diversity. Inferred crown group brachiopod and mollusc species (n = 76) do not appear until the Fortunian, ~537 Ma, radiate in the early Cambrian Stage 3 (~522 Ma), and with minimal loss of diversity at the Sinsk Event, continued to diversify into the Ordovician. The Sinsk Event also removed other probable stem groups, such as archaeocyath sponges. Notably, this diversification starts before, and extends across the Ediacaran/Cambrian boundary and the Basal Cambrian Carbon Isotope Excursion (BACE) interval (~541 to ~540 Ma), ascribed to a possible global perturbation of the carbon cycle. We therefore propose two phases of the Cambrian Explosion separated by the Sinsk extinction event, the first dominated by stem groups of phyla from the late Ediacaran, ~542 Ma, to early Cambrian stage 4, ~513 Ma, and the second marked by radiating bilaterian crown group species of phyla from ~513 Ma and extending to the Ordovician Radiation.
Changes in canine serum N-glycosylation as a result of infection with the heartworm parasite Dirofilaria immitis
Authors: Behrens Anna-Janina , Duke Rebecca M. , Petralia Laudine M. C. , Lehoux Sylvain , Carlow Clotilde K. S. , Taron Christopher H. , Foster Jeremy M.
Published: November 2018

Filariases are diseases caused by infection with filarial nematodes and transmitted by insect vectors. The filarial roundwormDirofilaria immitiscauses heartworm disease in dogs and other carnivores.D. immitisis closely related toOnchocerca volvulus,Wuchereria bancroftiandBrugia malayi, which cause onchocerciasis (river blindness) and lymphatic filariasis (elephantiasis) in humans and are neglected tropical diseases. Serum N-glycosylation is very sensitive to both pathological infections and changes in mammalian biology due to normal aging or lifestyle choices. Here, we report significant changes in the serum N-glycosylation profiles of dogs infected withD. immitis. Our data derive from analysis of serum from dogs with established patent infections and from a longitudinal infection study. Overall, galactosylation and core fucosylation increase, while sialylation decreases in infected dog sera. We also identify individual glycan structures that change significantly in their relative abundance during infection. Notably, the abundance of the most dominant N-glycan in canine serum (biantennary, disialylated A2G2S2) decreases by over 10 percentage points during the first 6 months of infection in each dog analyzed. This is the first longitudinal study linking changes in mammalian serum N-glycome to progression of a parasitic infection.
Geographical and temporal distribution of the residual clusters of human leptospirosis in China, 2005–2016
Authors: Dhewantara Pandji Wibawa , Mamun Abdullah Al , Zhang Wen-Yi , Yin Wen-Wu , Ding Fan , Guo Danhuai , Hu Wenbiao , Magalhães Ricardo J. Soares
Published: November 2018

Human leptospirosis outbreaks still persistently occur in part of China, indicating that leptospirosis remains an important zoonotic disease in the country. Spatiotemporal pattern of the high-risk leptospirosis cluster and the key characteristics of high-risk areas for leptospirosis across the country are still poorly understood. Using spatial analytical approaches, we analyzed 8,158 human leptospirosis cases notified during 2005–2016 across China to explore the geographical distribution of leptospirosis hotspots and to characterize demographical, ecological and socioeconomic conditions of high-risk counties for leptospirosis in China. During the period studied, leptospirosis incidence was geographically clustered with the highest rate observed in the south of the Province of Yunnan. The degree of spatial clustering decreased over time suggesting changes in local risk factors. However, we detected residual high-risk counties for leptospirosis including counties in the southwest, central, and southeast China. High-risk counties differed from low-risk counties in terms of its demographical, ecological and socioeconomic characteristics. In high-risk clusters, leptospirosis was predominantly observed on younger population, more males and farmers. Additionally, high-risk counties are characterized by larger rural and less developed areas, had less livestock density and crops production, and located at higher elevation with higher level of precipitation compare to low-risk counties. In conclusion, leptospirosis distribution in China appears to be highly clustered to a discrete number of counties highlighting opportunities for elimination; hence, public health interventions should be effectively targeted to high-risk counties identified in this study.
ROCK2, but not ROCK1 interacts with phosphorylated STAT3 and co-occupies TH17/TFH gene promoters in TH17-activated human T cells
Authors: Chen Wei , Nyuydzefe Melanie S. , Weiss Jonathan M. , Zhang Jingya , Waksal Samuel D. , Zanin-Zhorov Alexandra
Published: November 2018

Rho-associated coiled-coil kinase (ROCK)2 targeting down-regulates autoimmune responses in animal models and patients, however the underlying molecular mechanism is still an enigma. We report that ROCK2 binds phosphorylated-STAT3 and its kinase activity controls the formation of ROCK2/STAT3/JAK2 complex and optimal STAT3 phosphorylation in human CD4+ T cells during T helper 17 (TH17)-skewing. Moreover, chromatin-immunoprecipitation sequencing (ChIP-seq) analysis revealed that, genome-wide, about 70% of ROCK2 and STAT3 peaks overlapped and co-localized to several key genes controlling TH17 and T follicular helper (TFH) cell functions. Specifically, the co-occupancy of ROCK2 and STAT3 on the Irf4 and Bcl6 genes was validated by ChIP-qPCR analysis. Furthermore, the binding of ROCK2 to both the Irf4 and Bcl6 promoters was attenuated by STAT3 silencing as well as by selective ROCK2 inhibitor. Thus, the present study demonstrated previously unidentified evidence that ROCK2-mediated signaling in the cytosol provides a positive feed-forward signal for nuclear ROCK2 to be recruited to the chromatin by STAT3 and potentially regulates TH17/TFH gene transcription.
Ten-year experience of tricuspid valve replacement with the St. Jude medical valve
Authors: Zhu Xiliang , Luo Yi , Zhang Eryong , An Qi , Xiao Xijun , Dong Li , Guo Yingqiang , Dian Ke , Wu Zhong
Published: November 2018

Bioprosthetic valves for tricuspid valve replacement (TVR) have become increasingly popular in recent years, but mechanical valves remain valuable, particularly for the patients who want to avoid reoperation for bioprostheses malfunction. The aim of this study was to review our 10-year experience in adult patients who underwent TVR with the St. Jude Medical (SJM) valve. From 2005 to 2015, 265 TVRs with SJM valves were performed at our institution. The mean age at operation was 44.1 ± 9.7 years, and 207 cases (78.1%) were female. The mean follow-up was 4.9 ± 2.7 years. Preoperative atrial fibrillation was present in 199 cases (75.1%) and ascites in 26 (9.8%). Of all cases, 88.7% were characterized as New York Heart Association class III or IV. The hospital mortality was 6.4%. There were 9 deaths (3.8%) during late follow-up. The overall survival rates were 89.2% ± 2.2% at 5 years and 86.6% ± 2.9% at 10 years. The linearized rates of valve thrombosis and bleeding events were 0.8%/patient-year and 1.5%/patient-year, respectively. Three cases (1.3%) were reoperated due to prosthetic valve thrombosis. There was no reoperation for sperivalvular leakage and structural failure. The freedom from reoperation was 98.6% ± 0.8% at 5 years and 98.6% ± 0.8% at 10 years. The SJM valve in the tricuspid position is a reliable mechanical prosthesis with a low rate of valve thrombosis and reoperation. It is a reasonable choice for the patients who require mechanical valve replacement in the tricuspid position.
Breakdown of diffusivity–entropy scaling in colloidal glass-forming liquids
Authors: Li Bo , Xiao Xiuming , Lou Kai , Wang Shuxia , Wen Weijia , Wang Ziren
Published: November 2018

Glass is a liquid that has lost its ability to flow. Why this particular substance undergoes such a dramatic kinetic slowdown yet remains barely distinguishable in structure from its fluid state upon cooling constitutes the central question of glass transition physics. Here, we investigate the pathway of kinetic slowdown in glass-forming liquids that consist of monolayers of ellipsoidal or binary spherical colloids. In contrast to rotational motion, the dynamics of the translational motion begin to violently slow down at considerably low area fractions (ϕT). At ϕT, anomalous translation–rotation coupling is enhanced and the topography of the free energy landscape become rugged. Based on the positive correlation between ϕT and fragility, the measurement of ϕT offers a novel method for predicting glassy dynamics, circumventing the prohibitive increase in equilibrium times required in high-density regions. Our results highlight the role that thermodynamical entropy plays in glass transitions.
Raman spectroscopic features of primary cardiac microvascular endothelial cells (CMECs) isolated from the murine heart
Authors: Tott Szymon , Grosicki Marek , Klimas Beata , Augustynska Dominika , Chlopicki Stefan , Baranska Malgorzata
Published: November 2018

Gaining knowledge on the biochemical profile of primary endothelial cells on a subcellular level can contribute to better understanding of cardiovascular disease.