bluuebunny/crossref_metadata_2025 huggingface dataset:
Hematologic safety of chronic brain‐penetrating erythropoietin dosing in APP/PS1 mice
Authors: Sun Jiahong , Yang Joshua , Whitman Kathrine , Zhu Charlene , Cribbs David H. , Boado Ruben J. , Pardridge William M. , Sumbria Rachita K.
Published: October 2019

Introduction

Low blood‐brain barrier (BBB) penetration and hematopoietic side effects limit the therapeutic development of erythropoietin (EPO) for Alzheimer's disease (AD). A fusion protein of EPO and a chimeric monoclonal antibody targeting the mouse transferrin receptor (cTfRMAb) has been engineered. The latter drives EPO into the brain via receptor‐mediated transcytosis across the BBB and increases its peripheral clearance to reduce hematopoietic side effects of EPO. Our previous work shows the protective effects of this BBB‐penetrating EPO in AD mice but hematologic effects have not been studied. Herein, we investigate the hematologic safety and therapeutic effects of chronic cTfRMAb‐EPO dosing, in comparison to recombinant human EPO (rhu‐EPO), in AD mice.

Methods

Male APPswe PSEN1dE9 (APP/PS1) mice (9.5 months) were treated with saline (n = 11), and equimolar doses of cTfRMAb‐EPO (3 mg/kg, n = 7), or rhu‐EPO (0.6 mg/kg, n = 9) 2 days/week subcutaneously for 6 weeks, compared to saline‐treated wild‐type mice (n = 10). At 6 weeks, exploration and memory were assessed, and mice were sacrificed at 8 weeks. Spleens were weighed, and brains were evaluated for amyloid beta (Aβ) load and synaptophysin. Blood was collected at 4, 6 and 8 weeks for a complete blood count and white blood cells differential.

Results

cTfRMAb‐EPO transiently increased reticulocyte counts after 4 weeks, followed by normalization of reticulocytes at 6 and 8 weeks. rhu‐EPO transiently increased red blood cell count, hemoglobin and hematocrit, and significantly decreased mean corpuscular volume and reticulocytes at 4 weeks, which remained low at 6 weeks. At 8 weeks, a significant decline in red blood cell indices was observed with rhu‐EPO treatment. Exploration and cognitive deficits were significantly worse in APP/PS1‐rhu‐EPO mice. Both cTfRMAb‐EPO and rhu‐EPO decreased 6E10‐positive brain Aβ load; however, cTfRMAb‐EPO and not rhu‐EPO selectively reduced brain Aβ1‐42 and elevated synaptophysin expression.

Discussion

Chronic treatment with cTfRMAb‐EPO results in better hematologic safety, behavioral, and therapeutic indices compared with rhu‐EPO, supporting the development of this BBB‐penetrable EPO analog for AD.
CUTTING A PART FROM MANY MEASURES
Authors: BLAGOJEVIĆ PAVLE V. M. , PALIĆ NEVENA , SOBERÓN PABLO , ZIEGLER GÜNTER M.
Published: October 2019

Holmsen, Kynčl and Valculescu recently conjectured that if a finite set
$X$
with
$\ell n$
points in
$\mathbb{R}^{d}$
that is colored by
$m$
different colors can be partitioned into
$n$
subsets of
$\ell$
points each, such that each subset contains points of at least
$d$
different colors, then there exists such a partition of
$X$
with the additional property that the convex hulls of the
$n$
subsets are pairwise disjoint.

We prove a continuous analogue of this conjecture, generalized so that each subset contains points of at least
$c$
different colors, where we also allow
$c$
to be greater than
$d$
. Furthermore, we give lower bounds on the fraction of the points each of the subsets contains from
$c$
different colors. For example, when
$n\geqslant 2$
,
$d\geqslant 2$
,
$c\geqslant d$
with
$m\geqslant n(c-d)+d$
are integers, and
$\unicode[STIX]{x1D707}_{1},\ldots ,\unicode[STIX]{x1D707}_{m}$
are
$m$
positive finite absolutely continuous measures on
$\mathbb{R}^{d}$
, we prove that there exists a partition of
$\mathbb{R}^{d}$
into
$n$
convex pieces which equiparts the measures
$\unicode[STIX]{x1D707}_{1},\ldots ,\unicode[STIX]{x1D707}_{d-1}$
, and in addition every piece of the partition has positive measure with respect to at least
$c$
of the measures
$\unicode[STIX]{x1D707}_{1},\ldots ,\unicode[STIX]{x1D707}_{m}$
.
Management of Ventenata dubia in the inland Pacific Northwest with indaziflam
Authors: Koby Lindsay E. , Prather Timothy S. , Quicke Harold , Beuschlein Jared , Burke Ian C.
Published: October 2019

Ventenata [Ventenata dubia (Leers) Cross] is a winter annual grass relatively new to the inland Pacific Northwest that is capable of displacing desired vegetation. Indaziflam was evaluated for the management of V. dubia on two Conservation Reserve Program (CRP) sites near Moscow, ID, and Pullman, WA. While perennial grasses were dormant, applications of indaziflam in mixture with various herbicides were made in spring 2016. Treatment effects were evaluated for 2 yr by visual assessments of community composition and canopy cover of V. dubia and other non-weedy species (assessments occurred 3 to 6 mo after treatment, depending on location) and by representative cover class assessments. Biomass samples of all plant species were collected in the summer of 2017. Reduced V. dubia cover was observed in 2016, except when glyphosate was used alone. In 2017 indaziflam applied alone or in mixture with rimsulfuron effectively controlled V. dubia with minimal impact on desirable vegetation. Plant biomass from nontreated plots averaged 40 g m−2 for V. dubia and 100 to 179 g m−2 for perennial grasses. Plant biomass averaged <11 g m−2 for V. dubia and 371 to 490 g m−2 for perennial grasses when indaziflam at 102 g ai ha−1 plus glyphosate at 474 g ai ha−1 was applied. Smooth brome (Bromus inermis Leyss.) biomass was positively associated with the reduction of V. dubia, and there was a decrease in diversity associated with the removal of V. dubia through effective treatments. Indaziflam is an effective tool for the management of V. dubia in perennial grass stands, and spring applications of indaziflam should be in mixture with herbicides with POST activity.
The children of preterm survivors: shyness, parenting, and parental stress
Authors: Van Lieshout Ryan J. , Favotto Lindsay , Ferro Mark , Niccols Alison , Saigal Saroj , Morrison Katherine M. , Schmidt Louis A.
Published: October 2019

Extremely low birth weight (ELBW) survivors have higher rates of shyness, a risk factor for poorer outcomes across the life span. Due to advances in fetal and neonatal medicine, the first generation of ELBW survivors have survived to adulthood and become parents. However, no studies have investigated the transmission of their stress vulnerability to their offspring. We explored this phenomenon using a population-based cohort of ELBW survivors and normal birth weight (NBW) controls. Using data from three generations, we examined whether the shyness and parenting stress of ELBW and NBW participants (Generation 2) mediated the relation between the parenting style of their parents (Generation 1) and shyness in their offspring (Generation 3), and the extent to which exposure to perinatal adversity (Generation 2) moderated this mediating effect. We found that among ELBW survivors, parenting stress (in Generation 2) mediated the relation between overprotective parenting style in Generation 1 (grandparents) and child shyness in Generation 3. These findings suggest that perinatal adversity and stress may be transmitted to the next generation in humans, as reflected in their perceptions of their children as shy and socially anxious, a personality phenotype that may subsequently place their children at risk of later mental and physical health problems.
Predominant Sea Ice Fracture Zones Around Antarctica and Their Relation to Bathymetric Features
Authors: Reiser F. , Willmes S. , Hausmann U. , Heinemann G.
Published: October 2019

Sea ice is of substantial importance for the Southern Ocean, as it insulates the relatively warm ocean from the cold atmosphere. Due to mechanical stress induced by wind and ocean currents, sea ice leads occur, which are characterized by open water and thin ice causing an increase of energy and moisture fluxes between ocean and atmosphere. Furthermore, they contribute to the ice production and provide a habitat for animals. Thus, it is important to gain information about the temporal and spatial distribution of leads on a circum‐Antarctic scale. So far, no operational data set exists, which provides such information. We use thermal satellite imagery from the Moderate Resolution Imaging Spectroradiometer to derive the predominant lead patterns for 2003–2018, April–September. This study provides first results for the long‐term average lead frequencies in the Southern Ocean and discusses possible links to ocean currents, tides, and the bathymetry.
Modeling and Forecasting Aftershocks Can Be Improved by Incorporating Rupture Geometry in the ETAS Model
Authors: Guo Yicun , Zhuang Jiancang , Ogata Yosihiko
Published: October 2019

We implemented an extended version of the space‐time Epidemic‐Type Aftershock Sequence (ETAS) model, which simultaneously incorporates earthquake focal depths and rupture geometries of large earthquakes, and applied it to the 2016 Kumamoto earthquake sequence. Results show that the new model corrects the estimation biases of model parameters in the point source ETAS model. The reconstructed patterns of productivity density of aftershocks, along the mainshock rupture plane, form complementary patterns for coseismic slip in space and show significant spatiotemporal migrations. Large aftershocks tend to nucleate at the edges of high productivity density areas. The decay of direct aftershocks near the mainshock rupture is consistent with static stress changes caused by the mainshock. The forecasting capability of the ETAS model can be enhanced by considering the rupture geometries of mainshocks, especially for forecasting aftershocks in the first 1–2 days. In the simulation test, the incorporation of focal depths improves the forecasting resolution.
Misbehaving High‐Energy Electrons: Evidence in Support of Ubiquitous Wave‐Particle Interactions on Dayside Martian Closed Crustal Magnetic Fields
Authors: Shane Alexander , Liemohn Michael , Florie Corinne , Xu Shaosui
Published: October 2019

Multiple studies have reported either isotropic or trapped pitch angle distributions of high‐energy (>100 eV) electrons on closed crustal field lines on the dayside of Mars. These pitch angle distributions are not to be expected from collisional scattering and conservation of adiabatic invariants alone. We use 2 years of data from the Mars Atmosphere and Volatile EvolutioN mission to analyze the pitch angle distributions of superthermal electrons on dayside‐closed crustal magnetic fields and compare to results from an electron transport model. Low‐energy electrons (10–60 eV) have pitch angle distributions in agreement with modeling results, while high‐energy electrons (100–500 eV) do not. High‐energy electrons have a flux peak at perpendicular pitch angles which suggests there is a ubiquitous energization process occurring on crustal fields. Wave‐particle interactions seem to be the most likely candidate. Trapping of high‐energy electrons may impact the nightside ionosphere dynamics.
A Simulation Study on the Time Delay of Daytime Thermospheric Temperature Response to the 27‐Day Solar EUV Flux Variation
Authors: Ren Dexin , Lei Jiuhou , Wang Wenbin , Burns Alan , Luan Xiaoli , Dou Xiankang
Published: October 2019

In this study, the National Center for Atmospheric Research Thermosphere Ionosphere Electrodynamic General Circulation Model is used to explore the physical mechanisms of the time delay of daytime thermospheric temperature response to the 27‐day solar extreme ultraviolet (EUV) flux variation. The contributions from different physical processes to the time delay of thermospheric temperature response, the peak perturbation of the thermospheric temperature with respect to the peak of 27‐day solar EUV flux variation, were examined by diagnostically analyzing the thermospheric energy equation in a fixed local time frame. It was found that the time delay of the thermospheric temperature response to the 27‐day solar EUV flux variation corresponds to the time needed for the total heating and cooling rates to be balanced. This time is slightly later than the times of the peaks of both the heating and cooling rates. Furthermore, the global circulation in the upper atmosphere plays a significant role in the delayed response of thermospheric temperature to solar EUV flux variations. Our simulation results show that the time delay of thermospheric temperature response to the 27‐day solar EUV flux variation is about 0.5–0.8 day, depending on the amplitude of solar EUV flux variations.
A Simulation of the Field‐Aligned Plasma Transport in the Plasmaspheric Plume During the 2015 St. Patrick's Day Storm
Authors: Qiao Zheng , Yuan Zhigang , Tu Jiannan
Published: October 2019

In this paper, based on a calculated open E × B convection passage of a flux tube with subauroral polarization streams (SAPS) electric field involved, we use the Dynamic Fluid‐Kinetic model to simulate the transport of major ion species (H+, He+, and O+) along magnetic field line (field‐aligned) within the flux tube during the 2015 St. Patrick's Day storm. The drift trajectory is confirmed to be quite realistic based on observations and empirical models, meanwhile, the foot print of flux tube is initiated from subauroral latitudes toward polar latitudes along this drift pass. The Dynamic Fluid‐Kinetic simulation displays interesting temporal evolution of the field‐aligned plasma distribution at subauroral latitudes: The storm‐enhanced density region continuously provides upward ion flux filling into plasmasphere, but the equatorial mass loading in plasmaspheric plume increases at first and then decreases. Further analyses found that the SAPS particularly impact the field‐aligned transport of O+ particles from ionosphere to plasmasphere but have much less effect on H+ and He+ particles at subauroral latitudes, which causes significant enhancements of equatorial O+ density. The results show that the SAPS have significant effects on both drifting trajectory of the flux tube and associated field‐aligned ion dynamics. This work reveals intimate storm time interaction between the inner magnetosphere and ionosphere which may affect the dynamics in outer magnetosphere or even at magnetopause with flux tube convection.
Ocean Dynamics Shapes the Structure and Timing of Atlantic Equatorial Modes
Authors: Martín‐Rey Marta , Polo Irene , Rodríguez‐Fonseca Belén , Lazar Alban , Losada Teresa
Published: October 2019

A recent study has brought to light the co‐existence of two distinct Atlantic Equatorial Modes during negative phases of the Atlantic Multidecadal Variability: the Atlantic Niño and Horse‐Shoe (HS) mode. Nevertheless, the associated air‐sea interactions for HS mode have not been explored so far and the prevailing dynamic view of the Atlantic Niño has been questioned. Here, using a forced ocean model simulation, we find that for both modes, ocean dynamics is essential to explain the equatorial SST variations, while air‐sea fluxes control the off‐equatorial SST anomalies. Moreover, we demonstrate the key role played by ocean waves in shaping their distinct structure and timing. For the positive phase of both Atlantic Niño and HS, anomalous westerly winds trigger a set of equatorial downwelling Kelvin waves (KW) during spring‐summer. These dKWs deepen the thermocline, favouring the equatorial warming through vertical diffusion and horizontal advection. Remarkably, for the HS, an anomalous north‐equatorial wind stress curl excites an upwelling Rossby wave (RW), which propagates westward and is reflected at the western boundary becoming an equatorial upwelling KW. The uKW propagates to the east, activating the thermocline feedbacks responsible to cool the sea surface during summer months. This RW‐reflected mechanism acts as a negative feedback causing the early termination of the HS mode. Our results provide an improvement in the understanding of the TAV modes and emphasize the importance of ocean wave activity to modulate the equatorial SST variability. These findings could be very useful to improve the prediction of the Equatorial Modes.
The release of a distinct cell type from swarm colonies facilitates dissemination of Vibrio parahaemolyticus in the environment
Authors: Freitas Carolina , Glatter Timo , Ringgaard Simon
Published: October 2019

Bacteria experience changes in their environment and have developed various strategies to respond accordingly. To accommodate environmental changes, certain bacteria differentiate between specialized cell types. Vibrio parahaemolyticus is a marine bacterium, a worldwide human pathogen and the leading agent of seafood-borne gastroenteritis. It exists as swimmer or swarmer cells, specialized for life in liquid and on solid environments, respectively. Swarmer cells are characteristically highly elongated—a morphology important for swarming behavior. When attached to surfaces it forms swarm colonies, however, it is not known how cells within swarming populations respond to changes in the external milieu and how its distinct life cycle influences its ecological dissemination. The worldwide distribution of V. parahaemolyticus accentuates the need for understanding the factors contributing to its dissemination. Here we determine the stage-wise development of swarm colonies and show how the swarm colony architecture fluctuates with changing environmental conditions. Swarm colonies act as a continuous source of cells that are released from the swarm colony into the environment. Surprisingly, the cell length distribution of released cells was very homogenous and almost no long cells were detected, indicating that swarmer cells are not released into the liquid environment but stay surface attached during flooding. Released cells comprise a distinct cell type that is morphologically optimized for swimming behavior and is capable of spreading in the liquid environment and attach to new surfaces. Release of this distinct cell type facilitates the dissemination of V. parahaemolyticus in the environment and likely influences the ecology of this bacterium.
Extremophilic nitrite-oxidizing Chloroflexi from Yellowstone hot springs
Authors: Spieck Eva , Spohn Michael , Wendt Katja , Bock Eberhard , Shively Jessup , Frank Jeroen , Indenbirken Daniela , Alawi Malik , Lücker Sebastian , Hüpeden Jennifer
Published: October 2019

Nitrifying microorganisms occur across a wide temperature range from 4 to 84 °C and previous studies in geothermal systems revealed their activity under extreme conditions. Archaea were detected to be responsible for the first step of nitrification, but it is still a challenging issue to clarify the identity of heat-tolerant nitrite oxidizers. In a long-term cultivation approach, we inoculated mineral media containing ammonium and nitrite as substrates with biofilms and sediments of two hot springs in Yellowstone National Park (USA). The nitrifying consortia obtained at 70 °C consisted mostly of novel Chloroflexi as revealed by metagenomic sequencing. Among these, two deep-branching novel Chloroflexi were identified as putative nitrite-oxidizing bacteria (NOB) by the presence of nitrite oxidoreductase encoding genes in their genomes. Stoichiometric oxidation of nitrite to nitrate occurred under lithoautotrophic conditions, but was stimulated by organic matter. Both NOB candidates survived long periods of starvation and the more abundant one formed miniaturized cells and was heat resistant. This detection of novel thermophilic NOB exemplifies our still incomplete knowledge of nitrification, and indicates that nitrite oxidation might be an ancient and wide-spread form of energy conservation.
Archaeal nitrification is constrained by copper complexation with organic matter in municipal wastewater treatment plants
Authors: Gwak Joo-Han , Jung Man-Young , Hong Heeji , Kim Jong-Geol , Quan Zhe-Xue , Reinfelder John R , Spasov Emilie , Neufeld Josh D , Wagner Michael , Rhee Sung-Keun
Published: October 2019

Consistent with the observation that ammonia-oxidizing bacteria (AOB) outnumber ammonia-oxidizing archaea (AOA) in many eutrophic ecosystems globally, AOB typically dominate activated sludge aeration basins from municipal wastewater treatment plants (WWTPs). In this study, we demonstrate that the growth of AOA strains inoculated into sterile-filtered wastewater was inhibited significantly, in contrast to uninhibited growth of a reference AOB strain. In order to identify possible mechanisms underlying AOA-specific inhibition, we show that complex mixtures of organic compounds, such as yeast extract, were highly inhibitory to all AOA strains but not to the AOB strain. By testing individual organic compounds, we reveal strong inhibitory effects of organic compounds with high metal complexation potentials implying that the inhibitory mechanism for AOA can be explained by the reduced bioavailability of an essential metal. Our results further demonstrate that the inhibitory effect on AOA can be alleviated by copper supplementation, which we observed for pure AOA cultures in a defined medium and for AOA inoculated into nitrifying sludge. Our study offers a novel mechanistic explanation for the relatively low abundance of AOA in most WWTPs and provides a basis for modulating the composition of nitrifying communities in both engineered systems and naturally occurring environments.
Gene network analysis reveals a role for striatal glutamatergic receptors in dysregulated risk-assessment behavior of autism mouse models
Authors: Oron Oded , Getselter Dmitriy , Shohat Shahar , Reuveni Eli , Lukic Iva , Shifman Sagiv , Elliott Evan
Published: October 2019

Autism spectrum disorder (ASD) presents a wide, and often varied, behavioral phenotype. Improper assessment of risks has been reported among individuals diagnosed with ASD. Improper assessment of risks may lead to increased accidents and self-injury, also reported among individuals diagnosed with ASD. However, there is little knowledge of the molecular underpinnings of the impaired risk-assessment phenotype. In this study, we have identified impaired risk-assessment activity in multiple male ASD mouse models. By performing network-based analysis of striatal whole transcriptome data from each of these ASD models, we have identified a cluster of glutamate receptor-associated genes that correlate with the risk-assessment phenotype. Furthermore, pharmacological inhibition of striatal glutamatergic receptors was able to mimic the dysregulation in risk-assessment. Therefore, this study has identified a molecular mechanism that may underlie risk-assessment dysregulation in ASD.
Chromatin profiling of cortical neurons identifies individual epigenetic signatures in schizophrenia
Authors: Gusev Fedor E. , Reshetov Denis A. , Mitchell Amanda C. , Andreeva Tatiana V. , Dincer Aslihan , Grigorenko Anastasia P. , Fedonin Gennady , Halene Tobias , Aliseychik Maria , Filippova Elena , Weng Zhiping , Akbarian Schahram , Rogaev Evgeny I.
Published: October 2019

Both heritability and environment contribute to risk for schizophrenia. However, the molecular mechanisms of interactions between genetic and non-genetic factors remain unclear. Epigenetic regulation of neuronal genome may be a presumable mechanism in pathogenesis of schizophrenia. Here, we performed analysis of open chromatin landscape of gene promoters in prefrontal cortical (PFC) neurons from schizophrenic patients. We cataloged cell-type-based epigenetic signals of transcriptional start sites (TSS) marked by histone H3-K4 trimethylation (H3K4me3) across the genome in PFC from multiple schizophrenia subjects and age-matched control individuals. One of the top-ranked chromatin alterations was found in the major histocompatibility (MHC) locus on chromosome 6 highlighting the overlap between genetic and epigenetic risk factors in schizophrenia. The chromosome conformation capture (3C) analysis in human brain cells revealed the architecture of multipoint chromatin interactions between the schizophrenia-associated genetic and epigenetic polymorphic sites and distantly locatedHLA-DRB5andBTNL2genes. In addition, schizophrenia-specific chromatin modifications in neurons were particularly prominent for non-coding RNA genes, including an uncharacterizedLINC01115gene and recently identifiedBNRNA_052780. Notably, protein-coding genes with altered epigenetic state in schizophrenia are enriched for oxidative stress and cell motility pathways. Our results imply the rare individual epigenetic alterations in brain neurons are involved in the pathogenesis of schizophrenia.
Hippocampal proteomic changes of susceptibility and resilience to depression or anxiety in a rat model of chronic mild stress
Authors: Tang Min , Huang Haojun , Li Shuiming , Zhou Mi , Liu Zhao , Huang Rongzhong , Liao Wei , Xie Peng , Zhou Jian
Published: October 2019

Chronic stressful occurrences are documented as a vital cause of both depression and anxiety disorders. However, the stress-induced molecular mechanisms underlying the common and distinct pathophysiology of these disorders remains largely unclear. We utilized a chronic mild stress (CMS) rat model to differentiate and subgroup depression-susceptible, anxiety-susceptible, and insusceptible rats. The hippocampus was analyzed for differential proteomes by combining mass spectrometry and the isobaric tags for relative and absolute quantitation (iTRAQ) labeling technique. Out of 2593 quantified proteins, 367 were aberrantly expressed. These hippocampal protein candidates might be associated with susceptibility to stress-induced depression or anxiety and stress resilience. They provide the potential protein systems involved in various metabolic pathways as novel investigative protein targets. Further, independent immunoblot analysis identified changes in Por, Idh2 and Esd; Glo1, G6pdx, Aldh2, and Dld; Dlat, Ogdhl, Anxal, Tpp2, and Sdha that were specifically associated to depression-susceptible, anxiety-susceptible, or insusceptible groups respectively, suggesting that identical CMS differently impacted the mitochondrial and metabolic processes in the hippocampus. Collectively, the observed alterations to protein abundance profiles of the hippocampus provided significant and novel insights into the stress regulation mechanism in a CMS rat model. This might serve as the molecular basis for further studies that would contributed to a better understanding of the similarities and differences in pathophysiologic mechanisms underlying stress-induced depression or anxiety, and stress resiliency.
Two-dimensional inorganic molecular crystals
Authors: Han Wei , Huang Pu , Li Liang , Wang Fakun , Luo Peng , Liu Kailang , Zhou Xing , Li Huiqiao , Zhang Xiuwen , Cui Yi , Zhai Tianyou
Published: October 2019

Two-dimensional molecular crystals, consisting of zero-dimensional molecules, are very appealing due to their novel physical properties. However, they are mostly limited to organic molecules. The synthesis of inorganic version of two-dimensional molecular crystals is still a challenge due to the difficulties in controlling the crystal phase and growth plane. Here, we design a passivator-assisted vapor deposition method for the growth of two-dimensional Sb2O3 inorganic molecular crystals as thin as monolayer. The passivator can prevent the heterophase nucleation and suppress the growth of low-energy planes, and enable the molecule-by-molecule lateral growth along high-energy planes. Using Raman spectroscopy and in situ transmission electron microscopy, we show that the insulating α-phase of Sb2O3 flakes can be transformed into semiconducting β-phase under heat and electron-beam irradiation. Our findings can be extended to the controlled growth of other two-dimensional inorganic molecular crystals and open up opportunities for potential molecular electronic devices.
Transforming protein-polymer conjugate purification by tuning protein solubility
Authors: Baker Stefanie L. , Munasinghe Aravinda , Kaupbayeva Bibifatima , Rebecca Kang Nin , Certiat Marie , Murata Hironobu , Matyjaszewski Krzysztof , Lin Ping , Colina Coray M. , Russell Alan J.
Published: October 2019

Almost all commercial proteins are purified using ammonium sulfate precipitation. Protein-polymer conjugates are synthesized from pure starting materials, and the struggle to separate conjugates from polymer, native protein, and from isomers has vexed scientists for decades. We have discovered that covalent polymer attachment has a transformational effect on protein solubility in salt solutions. Here, protein-polymer conjugates with a variety of polymers, grafting densities, and polymer lengths are generated using atom transfer radical polymerization. Charged polymers increase conjugate solubility in ammonium sulfate and completely prevent precipitation even at 100% saturation. Atomistic molecular dynamic simulations show the impact is driven by an anti-polyelectrolyte effect from zwitterionic polymers. Uncharged polymers exhibit polymer length-dependent decreased solubility. The differences in salting-out are then used to simply purify mixtures of conjugates and native proteins into single species. Increasing protein solubility in salt solutions through polymer conjugation could lead to many new applications of protein-polymer conjugates.
Daily blue-light exposure shortens lifespan and causes brain neurodegeneration in Drosophila
Authors: Nash Trevor R. , Chow Eileen S. , Law Alexander D. , Fu Samuel D. , Fuszara Elzbieta , Bilska Aleksandra , Bebas Piotr , Kretzschmar Doris , Giebultowicz Jadwiga M.
Published: October 2019

Light is necessary for life, but prolonged exposure to artificial light is a matter of increasing health concern. Humans are exposed to increased amounts of light in the blue spectrum produced by light-emitting diodes (LEDs), which can interfere with normal sleep cycles. The LED technologies are relatively new; therefore, the long-term effects of exposure to blue light across the lifespan are not understood. We investigated the effects of light in the model organism, Drosophila melanogaster, and determined that flies maintained in daily cycles of 12-h blue LED and 12-h darkness had significantly reduced longevity compared with flies maintained in constant darkness or in white light with blue wavelengths blocked. Exposure of adult flies to 12 h of blue light per day accelerated aging phenotypes causing damage to retinal cells, brain neurodegeneration, and impaired locomotion. We report that brain damage and locomotor impairments do not depend on the degeneration in the retina, as these phenotypes were evident under blue light in flies with genetically ablated eyes. Blue light induces expression of stress-responsive genes in old flies but not in young, suggesting that cumulative light exposure acts as a stressor during aging. We also determined that several known blue-light-sensitive proteins are not acting in pathways mediating detrimental light effects. Our study reveals the unexpected effects of blue light on fly brain and establishes Drosophila as a model in which to investigate long-term effects of blue light at the cellular and organismal level.
Deciphering tea tree chloroplast and mitochondrial genomes of Camellia sinensis var. assamica
Authors: Zhang Fen , Li Wei , Gao Cheng-wen , Zhang Dan , Gao Li-zhi
Published: October 2019

Tea is the most popular non-alcoholic caffeine-containing and the oldest beverage in the world. In this study, we de novo assembled the chloroplast (cp) and mitochondrial (mt) genomes of C. sinensis var. assamica cv. Yunkang10 into a circular contig of 157,100 bp and two complete circular scaffolds (701719 bp and 177329 bp), respectively. We correspondingly annotated a total of 141 cp genes and 71 mt genes. Comparative analysis suggests repeat-rich nature of the mt genome compared to the cp genome, for example, with the characterization of 37,878 bp and 149 bp of long repeat sequences and 665 and 214 SSRs, respectively. We also detected 478 RNA-editing sites in 42 protein-coding mt genes, which are ~4.4-fold more than 54 RNA-editing sites detected in 21 protein-coding cp genes. The high-quality cp and mt genomes of C. sinensis var. assamica presented in this study will become an important resource for a range of genetic, functional, evolutionary and comparative genomic studies in tea tree and other Camellia species of the Theaceae family.
Linkage disequilibrium maps for European and African populations constructed from whole genome sequence data
Authors: Vergara-Lope Alejandra , Jabalameli M. Reza , Horscroft Clare , Ennis Sarah , Collins Andrew , Pengelly Reuben J.
Published: October 2019

Quantification of linkage disequilibrium (LD) patterns in the human genome is essential for genome-wide association studies, selection signature mapping and studies of recombination. Whole genome sequence (WGS) data provides optimal source data for this quantification as it is free from biases introduced by the design of array genotyping platforms. The Malécot-Morton model of LD allows the creation of a cumulative map for each choromosome, analogous to an LD form of a linkage map. Here we report LD maps generated from WGS data for a large population of European ancestry, as well as populations of Baganda, Ethiopian and Zulu ancestry. We achieve high average genetic marker densities of 2.3–4.6/kb. These maps show good agreement with prior, low resolution maps and are consistent between populations. Files are provided in BED format to allow researchers to readily utilise this resource.
Folding Free Energy Landscape of Ordered and Intrinsically Disordered Proteins
Authors: Chong Song-Ho , Ham Sihyun
Published: October 2019

Folding funnel is the essential concept of the free energy landscape for ordered proteins. How does this concept apply to intrinsically disordered proteins (IDPs)? Here, we address this fundamental question through the explicit characterization of the free energy landscapes of the representative α-helical (HP-35) and β-sheet (WW domain) proteins and of an IDP (pKID) that folds upon binding to its partner (KIX). We demonstrate that HP-35 and WW domain indeed exhibit the steep folding funnel: the landscape slope for these proteins is ca. −50 kcal/mol, meaning that the free energy decreases by ~5 kcal/mol upon the formation of 10% native contacts. On the other hand, the landscape of pKID is funneled but considerably shallower (slope of −24 kcal/mol), which explains why pKID is disordered in free environments. Upon binding to KIX, the landscape of pKID now becomes significantly steep (slope of −54 kcal/mol), which enables otherwise disordered pKID to fold. We also show that it is the pKID–KIX intermolecular interactions originating from hydrophobic residues that mainly confer the steep folding funnel. The present work not only provides the quantitative characterization of the protein folding free energy landscape, but also establishes the usefulness of the folding funnel concept to IDPs.
Membrane bound IL-21 based NK cell feeder cells drive robust expansion and metabolic activation of NK cells
Authors: Ojo Evelyn O. , Sharma Ashish Arunkumar , Liu Ruifu , Moreton Stephen , Checkley-Luttge Mary-Ann , Gupta Kalpana , Lee Grace , Lee Dean A. , Otegbeye Folashade , Sekaly Rafick-Pierre , de Lima Marcos , Wald David N.
Published: October 2019

NK cell adoptive therapy is a promising cancer therapeutic approach, but there are significant challenges that limiting its feasibility and clinical efficacy. One difficulty is the paucity of clinical grade manufacturing platforms to support the large scale expansion of highly active NK cells. We created an NK cell feeder cell line termed ‘NKF’ through overexpressing membrane bound IL-21 that is capable of inducing robust and sustained proliferation (>10,000-fold expansion at 5 weeks) of highly cytotoxic NK cells. The expanded NK cells exhibit increased cytotoxic function against a panel of blood cancer and solid tumor cells as compared to IL-2-activated non-expanded NK cells. The NKF-expanded NK cells also demonstrate efficacy in mouse models of human sarcoma and T cell leukemia. Mechanistic studies revealed that membrane-bound IL-21 leads to an activation of a STAT3/c-Myc pathway and increased NK cell metabolism with a shift towards aerobic glycolysis. The NKF feeder cell line is a promising new platform that enables the large scale proliferation of highly active NK cells in support of large scale third party NK cell clinical studies that have been recently intiatied. These results also provide mechanistic insights into how membrane-bound IL-21 regulates NK cell expansion.
Emergent dynamics of neuromorphic nanowire networks
Authors: Diaz-Alvarez Adrian , Higuchi Rintaro , Sanz-Leon Paula , Marcus Ido , Shingaya Yoshitaka , Stieg Adam Z. , Gimzewski James K. , Kuncic Zdenka , Nakayama Tomonobu
Published: October 2019

Neuromorphic networks are formed by random self-assembly of silver nanowires. Silver nanowires are coated with a polymer layer after synthesis in which junctions between two nanowires act as resistive switches, often compared with neurosynapses. We analyze the role of single junction switching in the dynamical properties of the neuromorphic network. Network transitions to a high-conductance state under the application of a voltage bias higher than a threshold value. The stability and permanence of this state is studied by shifting the voltage bias in order to activate or deactivate the network. A model of the electrical network with atomic switches reproduces the relation between individual nanowire junctions switching events with current pathway formation or destruction. This relation is further manifested in changes in 1/f power-law scaling of the spectral distribution of current. The current fluctuations involved in this scaling shift are considered to arise from an essential equilibrium between formation, stochastic-mediated breakdown of individual nanowire-nanowire junctions and the onset of different current pathways that optimize power dissipation. This emergent dynamics shown by polymer-coated Ag nanowire networks places this system in the class of optimal transport networks, from which new fundamental parallels with neural dynamics and natural computing problem-solving can be drawn.
Strategies to reduce genetic mosaicism following CRISPR-mediated genome edition in bovine embryos
Authors: Lamas-Toranzo I. , Galiano-Cogolludo B. , Cornudella-Ardiaca F. , Cobos-Figueroa J. , Ousinde O. , Bermejo-Álvarez P.
Published: October 2019

Genetic mosaicism is the presence of more than two alleles on an individual and it is commonly observed following CRISPR microinjection of zygotes. This phenomenon appears when DNA replication precedes CRISPR-mediated genome edition and it is undesirable because it reduces greatly the odds for direct KO generation by randomly generated indels. In this study, we have developed alternative protocols to reduce mosaicism rates following CRISPR-mediated genome edition in bovine. In a preliminary study we observed by EdU incorporation that DNA replication has already occurred at the conventional microinjection time (20 hpi). Aiming to reduce mosaicism appearance, we have developed three alternative microinjection protocols: early zygote microinjection (10 hpi RNA) or oocyte microinjection before fertilization with either RNA or Ribonucleoprotein delivery (0 hpi RNA or 0 hpi RNP). All three alternative microinjection protocols resulted in similar blastocyst and genome edition rates compared to the conventional 20 hpi group, whereas mosaicism rates were significantly reduced in all early delivery groups (~10–30% of edited embryos being mosaic depending on the loci) compared to conventional 20 hpi microinjection (100% mosaicism rate). These strategies constitute an efficient way to reduce the number of indels, increasing the odds for direct KO generation.
Utility of High-Sensitivity and Conventional Troponin in Patients Undergoing Transcatheter Aortic Valve Replacement: Incremental Prognostic Value to B-type Natriuretic Peptide
Authors: Kobayashi Yukari , Kim Juyong B. , Moneghetti Kegan J. , Fischbein Michael , Lee Anson , Watkins Claire A. , Yeung Alan C. , Liang David , Ozen Mehmet O. , Demirci Utkan , Bowen Raffick , Fearon William F. , Haddad Francois
Published: October 2019

High-sensitivity Troponin (hs-Tn) has emerged as a useful marker for patients with myocardial injury or heart failure. However, few studies have compared intermediate and hs-Tn in patients undergoing transcatheter aortic valve replacement (TAVR). Moreover, there remains uncertainty of which thresholds are the most useful for discriminating ventricular dysfunction or outcome. In this study we prospectively enrolled 105 patients with severe aortic stenosis (AS) who underwent TAVR as well as blood sampling for high-sensitivity (hs-TnI) and conventional troponin I (EXL-LOCI and RXL) assessment. Patients underwent comprehensive pre-procedure echocardiography. Ventricular dysfunction was defined using left ventricular mass index (LVMI), LV global longitudinal strain (LVGLS) and LV end-diastolic pressure. The mean age was 84.0 ± 8.7 years old and 60% were male sex with mean transaortic pressure gradient of 50.1 ± 16.0 mmHg and AVA of 0.63 ± 0.19 cm2. When using a threshold of 6 ng/L, 77% had positive hs-TnI while 27% had positive hs-TnI using recommended thresholds (16 ng/L for female and 34 ng/L for male). Troponin levels were higher in the presence of abnormal LV phenotypes. The strongest correlate of troponin was LVMI. During median follow-up of 375 days, 21 patients (20%) died. Lower threshold of hs-TnI and EXL-TnI was more discriminatory for overall mortality (Log-rank P = 0.03 for both), while higher threshold of hs-TnI (p = 0.75) and RXL-TnI were not (p = 0.30). Combining hs-TnI and BNP improved to predict long-term outcome (p = 0.004). In conclusion, hs-TnI levels correlated with the degree of LV dysfunction phenotypes. Furthermore, applying a lower threshold for hs-TnI performed better for outcome prediction than a recommended threshold in patients undergoing TAVR. Combining hs-TnI with BNP helped better risk stratification.
Long-term large-scale decline in relative abundances of butterfly and burnet moth species across south-western Germany
Authors: Habel Jan Christian , Trusch Robert , Schmitt Thomas , Ochse Michael , Ulrich Werner
Published: October 2019

Current studies have shown a severe general decline in insect species diversity, their abundance, and a biomass reduction of flying insects. Most of previous studies have been performed at single sites, or were spatially restricted at the landscape level. In this study, we analyse trends of species richness and shifts in species composition of butterflies and burnet moth species across the federal state of Baden-Württemberg in south-western Germany, covering an area of 35,750 km2. The data set consists of 233,474 records and covers a period from 1750 until today. We grouped species according to their species´ specific functional traits and analyse how species with different habitat requirements and behaviour respond to land-use changes over time. Our data document a significant loss of relative abundance for most species, especially since the 1950s until today. Species demanding specific habitat requirements are more seriously suffering under this trend than generalists. This in particular affects taxa adapted to extensively used xerothermic grasslands, bogs or other habitats maintained by traditional low-productivity agricultural practices of the past. Our data indicate large-scale decline in relative abundance of many butterfly and burnet moth species, which happened in particular during the past few decades.
Transcriptome profiling of mouse samples using nanopore sequencing of cDNA and RNA molecules
Authors: Sessegolo Camille , Cruaud Corinne , Da Silva Corinne , Cologne Audric , Dubarry Marion , Derrien Thomas , Lacroix Vincent , Aury Jean-Marc
Published: October 2019

Our vision of DNA transcription and splicing has changed dramatically with the introduction of short-read sequencing. These high-throughput sequencing technologies promised to unravel the complexity of any transcriptome. Generally gene expression levels are well-captured using these technologies, but there are still remaining caveats due to the limited read length and the fact that RNA molecules had to be reverse transcribed before sequencing. Oxford Nanopore Technologies has recently launched a portable sequencer which offers the possibility of sequencing long reads and most importantly RNA molecules. Here we generated a full mouse transcriptome from brain and liver using the Oxford Nanopore device. As a comparison, we sequenced RNA (RNA-Seq) and cDNA (cDNA-Seq) molecules using both long and short reads technologies and tested the TeloPrime preparation kit, dedicated to the enrichment of full-length transcripts. Using spike-in data, we confirmed that expression levels are efficiently captured by cDNA-Seq using short reads. More importantly, Oxford Nanopore RNA-Seq tends to be more efficient, while cDNA-Seq appears to be more biased. We further show that the cDNA library preparation of the Nanopore protocol induces read truncation for transcripts containing internal runs of T’s. This bias is marked for runs of at least 15 T’s, but is already detectable for runs of at least 9 T’s and therefore concerns more than 20% of expressed transcripts in mouse brain and liver. Finally, we outline that bioinformatics challenges remain ahead for quantifying at the transcript level, especially when reads are not full-length. Accurate quantification of repeat-associated genes such as processed pseudogenes also remains difficult, and we show that current mapping protocols which map reads to the genome largely over-estimate their expression, at the expense of their parent gene.
Endoplasmic reticulum stress differentially modulates the IL-6 family of cytokines in murine astrocytes and macrophages
Authors: Sanchez Cristina L. , Sims Savannah G. , Nowery John D. , Meares Gordon P.
Published: October 2019

In many diseases, misfolded proteins accumulate within the endoplasmic reticulum (ER), leading to ER stress. In response, the cell initiates the unfolded protein response (UPR) to reestablish homeostasis. Additionally, in response to ER stress, various cell types mount an inflammatory response involving interleukin (IL)-6. While IL-6 has been widely studied, the impact of ER stress on other members of the IL-6 cytokine family, including oncostatin (OSM), IL-11, ciliary neurotrophic factor (CNTF), and leukemia inhibitor factor (LIF) remains to be elucidated. Here, we have examined the expression of the IL-6 family cytokines in response to pharmacologically-induced ER stress in astrocytes and macrophages, which express IL-6 in response to ER stress through different mechanisms. Our findings indicate that, in astrocytes, ER stress regulates mRNA expression of the IL-6 family of cytokines that is, in part, mediated by PKR-like ER kinase (PERK) and Janus kinase (JAK) 1. Additionally, in astrocytes, CNTF expression was suppressed through a PERK-dependent mechanism. Macrophages display a different profile of expression of the IL-6 family that is largely independent of PERK. However, IL-6 expression in macrophages was dependent on JAK signaling. Overall, this study demonstrates the cell-specific and differential mechanisms controlling expression of the IL-6 family of cytokines in response to ER stress.