bluuebunny/crossref_metadata_2025 huggingface dataset:
Microvascular flow dictates the compromise between spatial resolution and acquisition time in Ultrasound Localization Microscopy
Authors: Hingot Vincent , Errico Claudia , Heiles Baptiste , Rahal Line , Tanter Mickael , Couture Olivier
Published: February 2019

Medical ultrasound is a widely used diagnostic imaging technique for tissues and blood vessels. However, its spatial resolution is limited to a sub-millimeter scale. Ultrasound Localization Microscopy was recently introduced to overcome this limit and relies on subwavelength localization and tracking of microbubbles injected in the blood circulation. Yet, as microbubbles follow blood flow, long acquisition time are required to detect them in the smallest vessels, leading to long reconstruction of the microvasculature. The objective of this work is to understand how blood flow limits acquisition time. We studied the reconstruction of a coronal slice of a rat’s brain during a continuous microbubble injection close to clinical concentrations. After acquiring 192000 frames over 4 minutes, we find that the biggest vessels can be reconstructed in seconds but that it would take tens of minutes to map the entire capillary network. Moreover, the appropriate characterization of flow profiles based on microbubble velocity within vessels is bound by even more stringent temporal limitations. As we use simple blood flow models to characterize its impact on reconstruction time, we foresee that these results and methods can be adapted to determine adequate microbubble injections and acquisition times in clinical and preclinical practice.
Soluble Graphene Nanosheets for the Sunlight-Induced Photodegradation of the Mixture of Dyes and its Environmental Assessment
Authors: Gunture  , Singh Anupriya , Bhati Anshu , Khare Prateek , Tripathi Kumud Malika , Sonkar Sumit Kumar
Published: February 2019

Currently, the air and water pollutions are presenting the most serious global concerns. Despite the well known tremendous efforts, it could be a promising sustainability if the black carbon (BC) soot can be utilized for the practical and sustainable applications. For this, the almost complete aqueous phase photodegradation of the three well-known organic pollutant dyes as crystal violet (CV); rhodamine B (RhB); methylene blue (MB) and their mixture (CV + RhB + MB), by using water-soluble graphene nanosheets (wsGNS) isolated from the BC soot under the influence of natural sunlight is described. The plausible mechanism behind the photocatalytic degradation of dyes and their mixture has been critically analyzed via the trapping of active species and structural analysis of photodegraded products. The impact of diverse interfering ions like Ca2+, Fe3+, SO42−, HPO42−, NO3−, and Cl− on the photodegradation efficiency of wsGNS was also investigated. Importantly, the environmental assessment of the whole process has been evaluated towards the growth of wheat plants using the treated wastewater. The initial studies for the fifteen days confirmed that growth of wheat plants was almost the same in the photodegraded wastewater as being noticed in the control sample, while in case of dyes contaminated water it showed the retarded growth. Using the natural sunlight, the overall sustainability of the presented work holds the potential for the utilization of pollutant soot in real-practical applications related to the wastewater remediation and further the practical uses of treated water.
Synthesis and Rational design of Europium and Lithium Doped Sodium Zinc Molybdate with Red Emission for Optical Imaging
Authors: Jain Neha , Paroha Ruchi , Singh Rajan K. , Mishra Siddhartha K. , Chaurasiya Shivendra K. , Singh R. A. , Singh Jai
Published: February 2019

Highly efficient fluorescent and biocompatible europium doped sodium zinc molybdate (NZMOE) nanoprobes were successfully synthesized via Polyol method. Non-radiative defect centres get reduced with Li+ co-doping in NZMOE nanoprobes. XRD spectra and Rietveld refinement confirmed successful incorporation of lithium ion and crystallinity was also improved with Li+ co-doping. The shape of phosphor is rod shaped, as determined by TEM. Significant enhancement in photoluminescence intensity was observed with 266, 395 and 465 nm excitations. Profound red emission was recorded for 5 at% Li+ co-doped NZMOE nanoprobes with 266 nm excitation. It shows high asymmetry ratio (~15), color purity (94.90%) and good quantum efficiency (~70%). Judd Ofelt parameters have been calculated to measure intensity parameters and radiative transition rates. In order to measure biocompatibility of the nanoprobes, cytotoxicity assays were performed with HePG2 cells. The fluorescence emitted from phosphor material treated HePG2 cells was also measured by Laser Scanning Confocal Microscopy. The bright red fluorescence in HePG2 cells treated with very low concentration (20 μg/ml) of phosphor material indicates that it could be a promising phosphor for biological detection or bio-imaging.
The glial sodium-potassium-2-chloride cotransporter is required for synaptic transmission in the Drosophila visual system
Authors: Stenesen Drew , Moehlman Andrew T. , Schellinger Jeffrey N. , Rodan Aylin R. , Krämer Helmut
Published: February 2019

The Drosophila Ncc69 gene encodes a Na+-K+-2Cl−-cotransporter (NKCC) that is critical for regulating intra- and extracellular ionic conditions in different tissues. Here, we show that the Ncc69 transporter is necessary for fly vision and that its expression is required non-autonomously in glia to maintain visual synaptic transmission. Flies mutant for Ncc69 exhibit normal photoreceptor depolarization in response to a light pulse but lack the ON and OFF-transients characteristic of postsynaptic responses of lamina neurons, indicating a failure in synaptic transmission. We also find that synaptic transmission requires the Ncc69 regulatory kinases WNK and Fray in glia. The ERG phenotype is associated with a defect in the recycling of the histamine neurotransmitter. Ncc69 mutants exhibit higher levels of the transport metabolite carcinine in lamina cartridges, with its accumulation most intense in the extracellular space. Our work reveals a novel role of glial NKCC transporters in synaptic transmission, possibly through regulating extracellular ionic conditions.
Identification and characterization of a factor Va-binding site on human prothrombin fragment 2
Authors: Friedmann Alexander P. , Koutychenko Anatoli , Wu Chengliang , Fredenburgh James C. , Weitz Jeffrey I. , Gross Peter L. , Xu Ping , Ni Feng , Kim Paul Y.
Published: February 2019

The fragment 2 domain (F2) of prothrombin and its interaction with factor (F) Va is known to contribute significantly to prothrombinase-catalyzed activation of prothrombin. The extent to which the F2-FVa interaction affects the overall thrombin generation, however, is uncertain. To study this interaction, nuclear magnetic resonance spectroscopy of recombinant F2 was used to identify seven residues within F2 that are significantly responsive to FVa binding. The functional role of this region in interacting with FVa during prothrombin activation was verified by the FVa-dependent inhibition of thrombin generation using peptides that mimic the same region of F2. Because six of the seven residues were within a 9-residue span, these were mutated to generate a prothrombin derivative (PT6). These mutations led to a decreased affinity for FVa as determined by surface plasmon resonance. When thrombin generation by an array of FXa containing prothrombinase components was monitored, a 54% decrease in thrombin generation was observed with PT6 compared with the wild-type, only when FVa was present. The functional significance of the specific low-affinity binding between F2 and FVa is discussed within the context of a dynamic model of molecular interactions between prothrombin and FVa engaging multiple contact sites.
Inheritance of Susceptibility to Malignant Blood Disorders
Authors: Jønsson Viggo , Awan Haneef , Jones Neil D. , Johannesen Tom B. , Steig Bjarni á , Andosdottir Gudrid , Tjønnfjord Geir E.
Published: February 2019

Malignant blood disorders depend on heritable susceptibility genes and occur in familial aggregations. We suggest a model of transgenerational segregation of the susceptibility genes based on the study of malignant blood disorders in Norwegian and Danish families with unrelated parents, and in the inbred Faroese population with related parents. This model, consisting of parental genomic imprinting and mother-son microchimerism, can explain the male predominance in most of the diseases, the predominance of affected parent-offspring when parents are not related, and the different modes of segregation in males and females. The model displays a specific pattern in the distribution of affected relatives for each diagnosis, viz. a characteristic distribution in the pedigrees of family members with malignant blood disorder related to the proband. Three such patterns, each reflecting a specific transgenerational passage, were identified: (1) alterations in the number of affected relatives in paternal lines alone, e.g. in patterns for probands with multiple myeloma; (2) alterations in the number of affected relatives in both paternal and maternal lines for probands with chronic lymphocytic leukemia; and (3) no alterations in the numbers of male and female affected relatives in the parental lines, e.g. for probands with some types of malignant lymphoma.
Accelerating Neutron Tomography experiments through Artificial Neural Network based reconstruction
Authors: Micieli Davide , Minniti Triestino , Evans Llion Marc , Gorini Giuseppe
Published: February 2019

Neutron Tomography (NT) is a non-destructive technique to investigate the inner structure of a wide range of objects and, in some cases, provides valuable results in comparison to the more common X-ray imaging techniques. However, NT is time consuming and scanning a set of similar objects during a beamtime leads to data redundancy and long acquisition times. Nowadays NT is unfeasible for quality checking study of large quantities of similar objects. One way to decrease the total scan time is to reduce the number of projections. Analytical reconstruction methods are very fast but under this condition generate streaking artifacts in the reconstructed images. Iterative algorithms generally provide better reconstruction for limited data problems, but at the expense of longer reconstruction time. In this study, we propose the recently introduced Neural Network Filtered Back-Projection (NN-FBP) method to optimize the time usage in NT experiments. Simulated and real neutron data were used to assess the performance of the NN-FBP method as a function of the number of projections. For the first time a machine learning based algorithm is applied and tested for NT image reconstruction problem. We demonstrate that the NN-FBP method can reliably reduce acquisition and reconstruction times and it outperforms conventional reconstruction methods used in NT, providing high image quality for limited datasets.
Effect of deuterium irradiation on graphite boronized in the NSTX-U tokamak
Authors: Bedoya F. , Allain J. P. , Dominguez-Gutierrez F. J. , Krstic P. S.
Published: February 2019

Boronization has been used in the National Spherical Torus-Upgrade (NSTX-U) as first wall conditioning technique. The technique decreased the oxygen impurities in the plasma and the O% on the Plasma Facing Components (PFC) as measured with an in-vacuo probe. Samples were extracted from tiles removed from the tokamak for post-mortem and controlled studies. Ex-vessel low energy and fluence D2+ and Ar+ irradiations were characterized in-situ to elucidate surface evolution of a cored graphite sample with an intrinsic concentration of boron from a tokamak environment. In addition, quadrupole mass spectrometer measurements of emitted D-containing species during irradiation, indicate potential retention of D by the boronized graphite interface and correlated back to the surface chemistry evolution. Classical Molecular Dynamics (CMD) simulations were used to investigate the chemistry of the B-C-O-D system. The results suggest that boron coatings retain oxygen by forming oxidized boron states in the presence of deuterium plasmas and corroborate empirical findings. A four times increase in the O% of the boron coatings was observed following in-situ deuterium exposures, in contrast with a reduction of equal magnitude observed after Ar irradiations. These results illustrate the complex chemistry driven by energetic ions at the edge of tokamaks plasmas on the PFCs.
Effect of chain flexibility on cell adhesion: Semi-flexible model-based analysis of cell adhesion to hydrogels
Authors: Lee Jooyoung , Song Boa , Subbiah Ramesh , Chung Justin J. , Choi U Hyeok , Park Kwideok , Kim Sang-Heon , Oh Seung Ja
Published: February 2019

Hydrogels have been developed and applied to various biomedical applications due to their biocompatibility. However, understanding of modulation between cells to hydrogel interface is still unclear, and parameters to explain the interaction are not sophisticated enough. In this report, we studied the effect of polymer chain flexibility on cell adhesion to various hydrogel constructs of collagen and fibrin gels. Specifically, novel method of semi-flexible model-based analysis confirmed that chain flexibility mediated microstructure of the hydrogels is a critical factor for cell adhesion on their surfaces. The proposed analysis showed possibility of more accurate prediction of biocompatibility of hydrogels, and it should be considered as one of the important criteria for polymer design and selections for enhancing both biocompatibility and biofunctionality.
The effect of 34-year continuous fertilization on the SOC physical fractions and its chemical composition in a Vertisol
Authors: Guo Zichun , Zhang Zhongbin , Zhou Hu , Wang Daozhong , Peng Xinhua
Published: February 2019

Reports regarding the effects of long-term organic and inorganic fertilization on the quantity and quality of soil organic carbon (SOC), particularly in Vertisols, are scarce. In this study, we combined SOC physical fractionation with 13C NMR spectroscopy technology to investigate the effect of 34 years of continuous fertilization on the SOC physical fractions and its chemical composition of 0–20 cm soil layer in a Vertisol. This study consisted of six treatments: no fertilization (control), chemical nitrogen, phosphorus and potassium fertilizers (NPK), low and high amounts of straw with chemical fertilizers (NPKLS and NPKHS), and pig or cattle manure with chemical fertilizers (NPKPM and NPKCM). Over 34 years of continuous fertilization, the SOC sequestration rate was from 0.08 Mg C ha−1 yr−1 in the control treatment to 0.66 Mg C ha−1 yr−1 in the NPKCM treatment, which was linearly related with the C input (P < 0.01). Of the five SOC physical fractions, two silt plus clay fractions (S + C_M, S + C_mM) dominated 74–92% of SOC, while three POM fractions (cPOM fPOM and iPOM) were only 8–26%. The two manure application treatments significantly increased all the SOC physical fractions except for the silt plus clay fraction within macroaggregates (S + C_M) compared with NPK treatment (P < 0.05), which was dependent on the larger amount of C input. Also, the two manure application treatments increased the levels of alkyl C and aromatic C but decreased O-alkyl C (P < 0.05), whereas the straw application (NPKLS and NPKHS) had no impact on the C functional groups (P > 0.05). Overall, the combination of animal manure with inorganic fertilization could enhance the SOC sequestration and alter its quantity and quality in Vertisols.
Premobilization of CD133+ cells by granulocyte colony- stimulating factor attenuates ischemic acute kidney injury induced by cardiopulmonary bypass
Authors: Li Xiaoqiang , Wan Qin , Min Jie , Duan Linjia , Liu Jin
Published: February 2019

Ischemic acute kidney injury (IAKI) is a common but severe complication after a cardiopulmonary bypass (CPB). Multiple studies have demonstrated that peripheral CD133+ or differentiated cells are able to home and repair the damaged tissues, but the number of available CD133+ cells is limited, and no efficient method published previously to mobilize them immediately. We analyzed the relationship between CD133+ cells and renal function in CPB patients, in addition, the efficacy of granulocyte colony-stimulating factor (G-CSF) pre-mobilized CD133+ cells in treating of mouse IAKI model have been investigated. In the clinical study, the prospective cohort study analyzed the correlation between BUN/Crea level and the peripheral CD133+ cell numbers. CPB was associated with postoperative renal dysfunction. The significant negative correlation was observed between patients’ Crea and CD133+ cells (P < 0.05). The proposed mechanism studies were performed on the mouse IAKI model. The experimental mice were treated by G-CSF to mobilize CD133+ cells before implementing CPB. Data on cell count, inflammatory index, renal function/injury, and CD133+ cell mobilization were analyzed. The result demonstrated that pretreatment by G-CSF resulted in tremendous increase in the number of mouse peripheral blood and renal CD133+ cells, significantly reduces renal tissue inflammation and dramatically improves the renal function after CPB. In summary, we concluded that premobilization of CD133+ cells abated CPB induced IAKI, by promoting both repairing damaged epithelium and by its anti-inflammatory activity. Our findings stress the remarkable applications of CD133+ or differentiated cells-based therapies for potential preventing ischemic acute kidney injury.
Asymmetric independence modeling identifies novel gene-environment interactions
Authors: Yu Guoqiang , Miller David J. , Wu Chiung-Ting , Hoffman Eric P. , Liu Chunyu , Herrington David M. , Wang Yue
Published: February 2019

Most genetic or environmental factors work together in determining complex disease risk. Detecting gene-environment interactions may allow us to elucidate novel and targetable molecular mechanisms on how environmental exposures modify genetic effects. Unfortunately, standard logistic regression (LR) assumes a convenient mathematical structure for the null hypothesis that however results in both poor detection power and type 1 error, and is also susceptible to missing factor, imperfect surrogate, and disease heterogeneity confounding effects. Here we describe a new baseline framework, the asymmetric independence model (AIM) in case-control studies, and provide mathematical proofs and simulation studies verifying its validity across a wide range of conditions. We show that AIM mathematically preserves the asymmetric nature of maintaining health versus acquiring a disease, unlike LR, and thus is more powerful and robust to detect synergistic interactions. We present examples from four clinically discrete domains where AIM identified interactions that were previously either inconsistent or recognized with less statistical certainty.
Cardiac molecular pathways influenced by doxorubicin treatment in mice
Authors: Bulten Ben F. , Sollini Martina , Boni Roberto , Massri Katrin , de Geus-Oei Lioe-Fee , van Laarhoven Hanneke W. M. , Slart Riemer H. J. A. , Erba Paola A.
Published: February 2019

Doxorubicin (DOX) is a potent chemotherapeutic with distinct cardiotoxic properties. Understanding the underlying cardiotoxic mechanisms on a molecular level would enable the early detection of cardiotoxicity and implementation of prophylactic treatment. Our goal was to map the patterns of different radiopharmaceuticals as surrogate markers of specific metabolic pathways induced by chemotherapy. Therefore, cardiac distribution of 99mTc-sestamibi, 99mTc-Annexin V, 99mTc-glucaric acid and [18F]FDG and cardiac expression of Bcl-2, caspase-3 and -8, TUNEL, HIF-1α, and p53 were assessed in response to DOX exposure in mice. A total of 80 mice (64 treated, 16 controls) were evaluated. All radiopharmaceuticals showed significantly increased uptake compared to controls, with peak cardiac uptake after one (99mTc-Annexin V), two (99mTc-sestamibi), three ([18F]FDG), or four (99mTc-glucaric acid) cycles of DOX. Strong correlations (p < 0.01) were observed between 99mTc-Annexin V, caspase 3 and 8, and TUNEL, and between [18F]FDG and HIF-1α. This suggests that the cardiac DOX response starts with apoptosis at low exposure levels, as indicated by 99mTc-Annexin V and histological apoptosis markers. Late process membrane disintegration can possibly be detected by 99mTc-sestamibi and 99mTc-glucaric acid. [18F]FDG signifies an early adaptive response to DOX, which can be further exploited clinically in the near future.
Decoupling a novel Trichormus variabilis-Synechocystis sp. interaction to boost phycoremediation
Authors: Abedi Sepideh , Astaraei Fatemeh Razi , Ghobadian Barat , Tavakoli Omid , Jalili Hassan , Greenwell H. Christopher , Cummins Ian , Chivasa Stephen
Published: February 2019

To conserve freshwater resources, domestic and industrial wastewater is recycled. Algal systems have emerged as an efficient, low-cost option for treatment (phycoremediation) of nutrient-rich wastewater and environmental protection. However, industrial wastewater may contain growth inhibitory compounds precluding algal use in phycoremediation. Therefore, extremophyte strains, which thrive in hostile environments, are sought-after. Here, we isolated such an alga - a strain of Synechocystis sp. we found to be capable of switching from commensal exploitation of the nitrogen-fixing Trichormus variabilis, for survival in nitrogen-deficient environments, to free-living growth in nitrate abundance. In nitrogen depletion, the cells are tethered to polysaccharide capsules of T. variabilis using nanotubular structures, presumably for nitrate acquisition. The composite culture failed to establish in industrial/domestic waste effluent. However, gradual exposure to increasing wastewater strength over time untethered Synechocystis cells and killed off T. variabilis. This switched the culture to a stress-acclimated monoculture of Synechocystis sp., which rapidly grew and flourished in wastewater, with ammonium and phosphate removal efficiencies of 99.4% and 97.5%, respectively. Therefore, this strain of Synechocystis sp. shows great promise for use in phycoremediation, with potential to rapidly generate biomass that can find use as a green feedstock for valuable bio-products in industrial applications.
Deciphering Z-scheme Charge Transfer Dynamics in Heterostructure NiFe-LDH/N-rGO/g-C3N4 Nanocomposite for Photocatalytic Pollutant Removal and Water Splitting Reactions
Authors: Nayak Susanginee , Parida K. M.
Published: February 2019

A series of heterostructure NiFe LDH/N-rGO/g-C3N4 nanocomposite were fabricated by combining calcinations-electrostatic self-assembly and hydrothermal steps. In this method, negatively charged N-rGO was electrostaticaly bonded to the self-assembled interface of n-n type g-C3N4/NiFe LDH hybrid. XRD and AFM results revealed successful formation of heterostructure nanocomposite due to the coupling effect of exfoliated NiFe LDH nanosheets with N-rGO and g-C3N4. Among the as synthesized heterostructure, CNNG3LDH performed superior photocatalytic activities towards 95 and 72% mineralization of RhB and phenol. Furthermore, CNNG3LDH could achieve the highest photocatalytic H2 evolution rate of 2508 μmolg−12h−1 and O2 evolution rate of 1280 μmolg−12h−1 under visible light irradiation. The CNNG3LDH possess lowest PL intensity, reduced arc of the Nyquist plot (43.8 Ώ) and highest photocurrent density (−0.97 mA cm−2) which revealed effective charge separation for superior photocatalytic activities. TRPL spectral results reveal the synergistic effect of layered component in CNNG3LDH for achievable higher life time of excitons of ~16.52 ns. In addition, N-rGO mediator based Z-scheme charge transfer mechanisms in CNNG3LDH were verified by the ESR and TA-PL studies. Enriched oxygen vacancy type defects in NiFe LDH and N-rGO mediated Z-scheme charge transfer mechanistic path strongly manifest the superior photocatalytic activities of the heterostructure materials.
Consequences of prenatal exposure to valproic acid in the socially monogamous prairie voles
Authors: Sailer L. , Duclot F. , Wang Z. , Kabbaj M.
Published: February 2019

Environmental risk factors contribute to autism spectrum disorders (ASD) etiology. In particular, prenatal exposure to the highly teratogenic anticonvulsant valproic acid (VPA) significantly increases ASD prevalence. Although significant discoveries on the embryopathology of VPA have been reported, its effects on the ability to form enduring social attachment—characteristic of ASD but uncommonly displayed by rats and mice—remains unknown. We aimed to examine the effects of prenatal VPA exposure in the social, monogamous prairie voles (Microtus ochrogaster). Compared to prenatal vehicle-exposed controls, prenatal VPA-exposed prairie voles had lower body weight throughout postnatal development, engaged in fewer social affiliative behaviors in a familial context, exhibited less social interactions with novel conspecifics, and showed enhanced anxiety-like behavior. Along these behavioral deficits, prenatal VPA exposure downregulated prefrontal cortex vasopressin receptor (V1aR) and methyl CpG-binding protein 2 (MeCP2) mRNA expression, but did not alter spine density in adults. Remarkably, adult social bonding behaviors, such as partner preference formation and selective aggression, were not disrupted by prenatal VPA exposure. Collectively, these studies suggest that, in this animal model, VPA alters only certain behavioral domains such as sex-naive anxiety and affiliative behaviors, but does not alter other domains such as social bonding with opposite sex individuals.
Polyacrylamide injection matrix for serial femtosecond crystallography
Authors: Park Jaehyun , Park Sehan , Kim Jangwoo , Park Gisu , Cho Yunje , Nam Ki Hyun
Published: February 2019

Serial femtosecond crystallography (SFX) provides opportunities to observe the dynamics of macromolecules without causing radiation damage at room temperature. Although SFX provides a biologically more reliable crystal structure than provided by the existing synchrotron sources, there are limitations due to the consumption of many crystal samples. A viscous medium as a carrier matrix reduces the flow rate of the crystal sample from the injector, thereby dramatically reducing sample consumption. However, the currently available media cannot be applied to specific crystal samples owing to reactions between the viscous medium and crystal sample. The discovery and characterisation of a new delivery medium for SFX can further expand its use. Herein, we report the preparation of a polyacrylamide (PAM) injection matrix to determine the crystal structure with an X-ray free-electron laser. We obtained 11,936 and 22,213 indexed images using 0.5 mg lysozyme and 1.0 mg thermolysin, respectively. We determined the crystal structures of lysozyme and thermolysin delivered in PAM at 1.7 Å and 1.8 Å resolutions. The maximum background scattering from PAM was lower than monoolein, a commonly used viscous medium. Our results show that PAM can be used as a sample delivery media in SFX studies.
Removing the no-analogue bias in modern accelerated tree growth leads to stronger medieval drought
Authors: Scharnweber Tobias , Heußner Karl-Uwe , Smiljanic Marko , Heinrich Ingo , van der Maaten-Theunissen Marieke , van der Maaten Ernst , Struwe Thomas , Buras Allan , Wilmking Martin
Published: February 2019

In many parts of the world, especially in the temperate regions of Europe and North-America, accelerated tree growth rates have been observed over the last decades. This widespread phenomenon is presumably caused by a combination of factors like atmospheric fertilization or changes in forest structure and/or management. If not properly acknowledged in the calibration of tree-ring based climate reconstructions, considerable bias concerning amplitudes and trends of reconstructed climatic parameters might emerge or low frequency information is lost. Here we present a simple but effective, data-driven approach to remove the recent non-climatic growth increase in tree-ring data. Accounting for the no-analogue calibration problem, a new hydroclimatic reconstruction for northern-central Europe revealed considerably drier conditions during the medieval climate anomaly (MCA) compared with standard reconstruction methods and other existing reconstructions. This demonstrates the necessity to account for fertilization effects in modern tree-ring data from affected regions before calibrating reconstruction models, to avoid biased results.
Comparison between chronic hepatitis B patients with untreated immune-tolerant phase vs. those with virological response by antivirals
Authors: Lee Hye Won , Kim Seung Up , Baatarkhuu Oidov , Park Jun Yong , Kim Do Young , Ahn Sang Hoon , Han Kwang-Hyub , Kim Beom Kyung
Published: February 2019

Routine nucleos(t)ide analogs (NUCs) have not yet been recommended for patients with immune-tolerant (IT) phase in chronic hepatitis B virus (HBV) infection. We aimed to evaluate prognosis of patients in untreated IT-phase (UIT group), compared to those in immune-active phase who achieved virological response by NUCs according to guidelines (VR group). Between 2006 and 2012, patients in UIT or VR groups were included. Cumulative risks of HCC and liver-related events (LREs) development were assessed. Furthermore, propensity-score was calculated based upon age, gender, diabetes and liver stiffness. UIT group (n = 126) showed younger age, lower proportion of male gender and lower LS than VR group (n = 641). UIT group had similar 10-year cumulative risks of HCC (2.7% vs. 2.9%, p = 0.704) and LRE (4.6% vs. 6.1%, p = 0.903) development, compared to VR group. When we re-defined UIT group by the lower ALT cut-offs, 10-year cumulative risks of HCC and LRE development were 2.9% and 4.8%, respectively. Using propensity-score matching and inverse probability treatment weighting analysis, similar results were reproduced. UIT group consistently had similar prognosis compared to VR group. Therefore, further large-scale prospective studies in order to verify rationales of routine NUCs in UIT group are still required.
Emergence of Two different recombinant PRRSV strains with low neutralizing antibody susceptibility in China
Authors: Han Guangwei , Xu Huiling , Wang Kexiong , He Fang
Published: February 2019

PRRSV causes major economic loss in global swine industry. 41 of 131 (31.29%) tissue samples collected from pig farms in central and east China from 2016 to 2017 were confirmed as PRRSV positive in RT-PCR. Base on phylogenetic analysis for ORF5 and ORF6, 3 isolates closely related to QYYZ strain form a new subgroup IV, while 3 other ones were clustered into subgroup III, represented by NADC30. Numerous amino acid substitutions involved in viral neutralization susceptibility were identified in GP5 among these isolates. Two emerging PRRSV strains (ZJnb16-2, SDbz16-2) were successfully isolated and sequenced. ZJnb16-2 was identified as a recombinant virus between strain QYYZ and JXA1 while SDbz16-2 was an inter-subgenotype recombinant virus of strains NADC30 and JXA1. As shown in the pathogenicity evaluation in piglets, ZJnb16-2 is highly pathogenic while SDbz16-2 is mild. Hyper-immune sera against major vaccine strains HUN4-F112 and JK-100 failed to neutralize either ZJnb16-2 or SDbz16-2. Only 0.8–2.0% of pig serum samples which were confirmed as PRRSV-positive with commercial ELISA kits presented neutralization reactivity against either ZJnb16-2 or SDbz16-2. The study confirmed that the viral genomic recombination contributes to the emergence of new pathogenic PRRSVs in China, which may escape from the protective immunity elicited by the conventional vaccines, highlighting the necessity in updates of vaccine strains and the need for a universal vaccine against PRRSV.
Transcriptomic studies and assessment of Yersinia pestis reference genes in various conditions
Authors: Koch Lionel , Poyot Thomas , Schnetterle Marine , Guillier Sophie , Soulé Estelle , Nolent Flora , Gorgé Olivier , Neulat-Ripoll Fabienne , Valade Eric , Sebbane Florent , Biot Fabrice
Published: February 2019

Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) is a very sensitive widespread technique considered as the gold standard to explore transcriptional variations. While a particular methodology has to be followed to provide accurate results many published studies are likely to misinterpret results due to lack of minimal quality requirements. Yersinia pestis is a highly pathogenic bacterium responsible for plague. It has been used to propose a ready-to-use and complete approach to mitigate the risk of technical biases in transcriptomic studies. The selection of suitable reference genes (RGs) among 29 candidates was performed using four different methods (GeNorm, NormFinder, BestKeeper and the Delta-Ct method). An overall comprehensive ranking revealed that 12 following candidate RGs are suitable for accurate normalization: gmk, proC, fabD, rpoD, nadB, rho, thrA, ribD, mutL, rpoB, adk and tmk. Some frequently used genes like 16S RNA had even been found as unsuitable to study Y. pestis. This methodology allowed us to demonstrate, under different temperatures and states of growth, significant transcriptional changes of six efflux pumps genes involved in physiological aspects as antimicrobial resistance or virulence. Previous transcriptomic studies done under comparable conditions had not been able to highlight these transcriptional modifications. These results highlight the importance of validating RGs prior to the normalization of transcriptional expression levels of targeted genes. This accurate methodology can be extended to any gene of interest in Y. pestis. More generally, the same workflow can be applied to identify and validate appropriate RGs in other bacteria to study transcriptional variations.
The parental co-immunization hypothesis: An observational competing risks analysis
Authors: Portela Miguel , Schweinzer Paul
Published: February 2019

The main interest of this study is the hypothesis that contact with small children may be beneficial for the parents’ later health and mortality (because of changes in their immune system). For this purpose, we document the relationship of a set of individual characteristics—including parenthood and marital state—and socioeconomic status with an individual’s cause of death. Using a novel and rich data set made available by the Office for National Statistics Longitudinal Study (ONS-LS), which follows 1% of the population of England and Wales along five census waves 1971, 1981, 1991, 2001, and 2011, our competing risks analysis yields several striking results: (1) Females with children have a 72.5% reduced risk of dying of cancer compared to childless females (for childless females of age 70, this corresponds to a risk of dying of cancer of 1.3% compared to a risk of about 1.3 × 0.275 = 0.4% for females with children). (2) Males have a 171% increased chance of dying of cancer when they are married (e.g., a baseline probability of 1.2% when 75 year old) compared to unmarried males. (3) Females with children have only a 34% risk of dying of heart disease (corresponding to a conditional probability of 0.3% when aged 65) relative to females without children and (4) a 53% chance of dying of infections (i.e., 0.1% at 65 years of age) compared to the risk for females without children. (5) At the same age, married men have an increased expectation of 123% of dying of heart disease (corresponding to an expected death probability of 0.7%) compared to unmarried men. (6) High income and house ownership is always associated with higher survival but less so than having children. While these results document a relationship between the presence of children and mortality, the specific transmission mechanisms remain unclear and we cannot make causality assertions.
Octa-repeat domain of the mammalian prion protein mRNA forms stable A-helical hairpin structure rather than G-quadruplexes
Authors: Czech Andreas , Konarev Petr V. , Goebel Ingrid , Svergun Dmitri I. , Wills Peter R. , Ignatova Zoya
Published: February 2019

Misfolding and aggregation of prion protein (PrP) causes neurodegenerative diseases like Creutzfeldt-Jakob disease (CJD) and scrapie. Besides the consensus that spontaneous conversion of normal cellular PrPCinto misfolded and aggregating PrPScis the central event in prion disease, an alternative hypothesis suggests the generation of pathological PrPScby rare translational frameshifting events in the octa-repeat domain of the PrP mRNA. Ribosomal frameshifting most commonly relies on a slippery site and an adjacent stable RNA structure to stall translating ribosome. Hence, it is crucial to unravel the secondary structure of the octa-repeat domain of PrP mRNA. Each of the five octa-repeats contains a motif (GGCGGUGGUGGCUGGG) which alonein vitroforms a G-quadruplex. Since the propensity of mRNA to form secondary structure depends on the sequence context, we set to determine the structure of the complete octa-repeat region. We assessed the structure of full-length octa-repeat domain of PrP mRNA using dynamic light scattering (DLS), small angle X-ray scattering (SAXS), circular dichroism (CD) spectroscopy and selective 2′-hydroxyl acylation analysis by primer extension (SHAPE). Our data show that the PrP octa-repeat mRNA forms stable A-helical hairpins with no evidence of G-quadruplex structure even in the presence of G-quadruplex stabilizing agents.
The prevalence of pre-diabetes and diabetes and their associated factors in Northeast China: a cross-sectional study
Authors: Wang Rui , Zhang Peng , Li Zhijun , Lv Xin , Cai Hongfei , Gao Chunshi , Song Yuanyuan , Yu Yaqin , Li Bo , Cui Youbin
Published: February 2019

This study investigates the prevalence of pre-diabetes and diabetes and their associated risk factors among adults in Northeast China. A multistage stratified cluster sampling method was used to select adults from Jilin Province. Out of an initial recruitment of 23,050 individuals, 21,435 participants completed an interview and medical examination. The estimated prevalence of diabetes and pre-diabetes were 9.1% and 19.8%, respectively. The prevalence of hypertension, dyslipidemia, and obesity were the highest in participants with previously diagnosed diabetes. Participants who were previously diagnosed with diabetes were more likely to be aware of their hypertension and dyslipidemia status. Participants who were older, male, more educated, or who were widows or widowers were at greater risk for pre-diabetes. Similarly, those who were current drinkers or smokers, had higher BMI or waist circumference, had a family history of diabetes, or who reported they lived in urban areas or had low physical activity levels had increased pre-diabetes risk. The observed levels of diabetes and pre-diabetes in this study indicate that the medical authority needs to focus more attention in this area, and that health monitoring is essential to improving the health awareness of its residents.
Effects of dominance and prestige based social status on competition for attentional resources
Authors: Roberts Ashton , Palermo Romina , Visser Troy A. W.
Published: February 2019

Social status can be attained through either dominance (coercion and intimidation) or prestige (skill and respect). Individuals high in either of these status pathways are known to more readily attract gaze and covert spatial attention compared to their low-status counterparts. However it is not known if social status biases allocation of attentional resources to competing stimuli. To address this issue, we used an attentional blink paradigm to explore non-spatial attentional biases in response to face stimuli varying in dominance and prestige. Results from a series of studies consistently indicated that participants were biased towards allocating attention to low- relative to high- dominance faces. We also observed no effects of manipulating prestige on attentional bias. We attribute our results to the workings of comparatively early processing stages, separate from those mediating spatial attention shifts, which are tuned to physical features associated with low dominance. These findings challenge our current understanding of the impact of social status on attentional competition.
Graphene Oxide Induced Surface Modification for Functional Separators in Lithium Secondary Batteries
Authors: Kim Ju Young , Shin Dong Ok , Kim Kwang Man , Oh Jimin , Kim Jumi , Kang Seok Hun , Lee Myeong Ju , Lee Young-Gi
Published: February 2019

Functional separators, which have additional functions apart from the ionic conduction and electronic insulation of conventional separators, are highly in demand to realize the development of advanced lithium ion secondary batteries with high safety, high power density, and so on. Their fabrication is simply performed by additional deposition of diverse functional materials on conventional separators. However, the hydrophobic wetting nature of conventional separators induces the polarity-dependent wetting feature of slurries. Thus, an eco-friendly coating process of water-based slurry that is highly polar is hard to realize, which restricts the use of various functional materials dispersible in the polar solvent. This paper presents a surface modification of conventional separators that uses a solution-based coating of graphene oxide with a hydrophilic group. The simple method enables the large-scale tuning of surface wetting properties by altering the morphology and the surface polarity of conventional separators, without significant degradation of lithium ion transport. On the surface modified separator, superior wetting properties are realized and a functional separator, applicable to lithium metal secondary batteries, is demonstrated as an example. We believe that this simple surface modification using graphene oxide contributes to successful fabrication of various functional separators that are suitable for advanced secondary batteries.
Exploration of inositol 1,4,5-trisphosphate (IP3) regulated dynamics of N-terminal domain of IP3 receptor reveals early phase molecular events during receptor activation
Authors: Chandran Aneesh , Chee Xavier , Prole David L. , Rahman Taufiq
Published: February 2019

Inositol 1, 4, 5-trisphosphate (IP3) binding at the N-terminus (NT) of IP3 receptor (IP3R) allosterically triggers the opening of a Ca2+-conducting pore located ~100 Å away from the IP3-binding core (IBC). However, the precise mechanism of IP3 binding and correlated domain dynamics in the NT that are central to the IP3R activation, remains unknown. Our all-atom molecular dynamics (MD) simulations recapitulate the characteristic twist motion of the suppressor domain (SD) and reveal correlated ‘clam closure’ dynamics of IBC with IP3-binding, complementing existing suggestions on IP3R activation mechanism. Our study further reveals the existence of inter-domain dynamic correlation in the NT and establishes the SD to be critical for the conformational dynamics of IBC. Also, a tripartite interaction involving Glu283-Arg54-Asp444 at the SD – IBC interface seemed critical for IP3R activation. Intriguingly, during the sub-microsecond long simulation, we observed Arg269 undergoing an SD-dependent flipping of hydrogen bonding between the first and fifth phosphate groups of IP3. This seems to play a major role in determining the IP3 binding affinity of IBC in the presence/absence of the SD. Our study thus provides atomistic details of early molecular events occurring within the NT during and following IP3 binding that lead to channel gating.
BRAF V600E and SRC mutations as molecular markers for predicting prognosis and conversion surgery in Stage IV colorectal cancer
Authors: Shimada Yoshifumi , Muneoka Yusuke , Nagahashi Masayuki , Ichikawa Hiroshi , Tajima Yosuke , Hirose Yuki , Ando Takuya , Nakano Masato , Sakata Jun , Kameyama Hitoshi , Takii Yasumasa , Ling Yiwei , Okuda Shujiro , Takabe Kazuaki , Wakai Toshifumi
Published: February 2019

Comprehensive genomic sequencing (CGS) enables us to detect numerous genetic alterations in a single assay. We aimed to identify molecular markers for predicting prognosis and conversion surgery in Stage IV colorectal cancer (CRC) using CGS. One-hundred eleven patients with Stage IV CRC who underwent primary tumor resection were analyzed. We retrospectively investigated genetic alterations using CGS of a 415-gene panel. Clinicopathological variables and genetic alterations were analyzed to identify independent prognostic factors of overall survival (OS). Forty-five of 111 patients had R0 resection; of these, 11 patients underwent conversion surgery. Univariate and multivariate analyses identified histopathological grade 3, R0 resection, BRAF V600E mutation, and SRC mutation as independent prognostic factors for OS (P = 0.041, P = 0.013, P = 0.005, and P = 0.023, respectively). BRAF V600E and SRC mutations were mutually exclusive, and SRC mutation was significantly associated with left-sided tumor and liver metastasis compared to BRAF V600E mutation (P = 0.016 and P = 0.025, respectively). Eleven of the 74 initially unresectable patients underwent conversion surgery for R0 resection, yet none harbored BRAF V600E or SRC mutations. BRAF V600E and SRC mutations are important molecular markers which can predict prognosis and conversion surgery in Stage IV CRC.
The Limits of Earthquake Early Warning Accuracy and Best Alerting Strategy
Authors: Minson Sarah E. , Baltay Annemarie S. , Cochran Elizabeth S. , Hanks Thomas C. , Page Morgan T. , McBride Sara K. , Milner Kevin R. , Meier Men-Andrin
Published: February 2019

We explore how accurate earthquake early warning (EEW) can be, given our limited ability to forecast expected shaking even if the earthquake source is known. Because of the strong variability of ground motion metrics, such as peak ground acceleration (PGA) and peak ground velocity (PGV), we find that correct alerts (i.e., alerts that accurately estimate the ground motion will be above a predetermined damage threshold) are not expected to be the most common EEW outcome even when the earthquake magnitude and location are accurately determined. Infrequently, ground motion variability results in a user receiving a false alert because the ground motion turned out to be significantly smaller than the system expected. More commonly, users will experience missed alerts when the system does not issue an alert but the user experiences potentially damaging shaking. Despite these inherit limitations, EEW can significantly mitigate earthquake losses for false-alert-tolerant users who choose to receive alerts for expected ground motions much smaller than the level that could cause damage. Although this results in many false alerts (unnecessary alerts for earthquakes that do not produce damaging ground shaking), it minimizes the number of missed alerts and produces overall optimal performance.
Mutations in sigma 70 transcription factor improves expression of functional eukaryotic membrane proteins in Escherichia coli
Authors: Tomatis Pablo Emiliano , Schütz Marco , Umudumov Elina , Plückthun Andreas
Published: February 2019

Eukaryotic integral membrane proteins (IMPs) are difficult to study due to low functional expression levels. To investigate factors for efficient biogenesis of eukaryotic IMPs in the prokaryotic model organism Escherichia coli, important, e.g., for isotope-labeling for NMR, we selected for E. coli cells expressing high levels of functional G protein-coupled receptors (GPCRs) by FACS. Utilizing an E. coli strain library with all non-essential genes systematically deleted, we unexpectedly discovered upon whole-genome sequencing that the improved phenotype was not conferred by the deleted genes but by various subtle alterations in the “housekeeping” sigma 70 factor (RpoD). When analyzing effects of the rpoD mutations at the transcriptome level we found that toxic effects incurred on wild-type E. coli during receptor expression were diminished by two independent and synergistic effects: a slower but longer-lasting GPCR biosynthesis and an optimized transcriptional pattern, augmenting growth and expression at low temperature, setting the basis for further bacterial strain engineering.