bluuebunny/crossref_metadata_2025 huggingface dataset:
Biochemical and Biological Properties of a Recombinant Tissue-Type Plasminogen Activator Derived from the Rat JMI-229 Cell Line
Authors: Lijnen H R , Webb P D , Van Hoef B , Cock F De , Stassen J M , Prior S D , Collen D
Published: July 2018

Recombinant tissue-type plasminogen activator (rt-PA), produced by expression of the genomic t-PA DNA from the JMI-229 cell line, which is of rat origin, in the host cell line, was purified to homogeneity. JMI-229 rt-PA was obtained essentially as a single chain molecule which was quantitatively converted to a two-chain moiety by treatment with plasmin. The plasminogen activating potential of single chain JMI-229 rt-PA was 5-fold lower than that of commercially available human rt-PA (Actilyse®) in the absence of fibrin, but comparable in the presence of fibrin; it showed a concentration-dependent binding to fibrin, with a significantly more pronounced binding than Actilyse® at low fibrin concentration (85 ± 8% versus 20 ± 7% at 0.025 mg/ml fibrin; p = 0.004). In human plasma in the absence of fibrin, the concentrations of both single chain and two-chain JMI-229 rt-PA required to induce 50% fibrinogen degradation in 2 h, were about 15-fold higher than those of Actilyse®. Both single chain and two-chain forms of JMI-229 rt-PA and of Actilyse® induced a similar time- and concentration-dependent lysis of a 125I-fibrin-labeled plasma clot immersed in human plasma, in the absence of significant systemic fibrinolytic activation. Equally effective concentrations (causing 50% clot lysis in 2 h) were 0.11 or 0.10 pg/ml for single chain or two-chain JMI-229 rt-PA, as compared to 0.11 or 0.15 pg/ml for single chain or two-chain Actilyse®. Continuous infusion over 60 min of single chain JMI-229 rt-PA or Actilyse® in hamsters with a 125I-fibrin-labeled pulmonary embolus, revealed a very similar thrombolytic potency (clot lysis versus dose) and specific thrombolytic activity (clot lysis versus steady state plasma antigen level of t-PA). The initial plasma half-life following intravenous bolus injection of 0.10 mg/kg in hamsters was equally short for JMI-229 rt-PA or Actilyse® (1.2 or 1.4 min respectively).

It is concluded that JMI-229 rt-PA has a higher fibrin-affinity and a higher fibrin-specificity in human plasma in the absence of fibrin than Actilyse®, but a comparable thrombolytic potency in a hamster pulmonary embolism model.
Binding of Human Platelet Glycoprotein lb and Actin to Fragments of Actin-Binding Protein
Authors: Aakhus Anne M , Wilkinson J Michael , Solum Nils Olav
Published: July 2018

Actin-binding protein (ABP) is degraded into fragments of 190 and 90 kDa by calpain. A monoclonal antibody (MAb TI10) against the 90 kDa fragment of ABP coprecipitated with the glycoprotein lb (GP lb) peak observed on crossed immunoelectrophoresis of Triton X-100 extracts of platelets prepared without calpain inhibitors. MAb PM6/317 against the 190 kDa fragment was not coprecipitated with the GP lb peak under such conditions. The 90 kDa fragment was adsorbed on protein A agarose from extracts that had been preincubated with antibodies to GP lb. This supports the idea that the GP Ib-ABP interaction resides in the 90 kDa region of ABP. GP lb was sedimented with the Triton-insoluble actin filaments in trace amounts only, and only after high speed centrifugation (100,000 × g, 3 h). Both the 190 kDa and the 90 kDa fragments of ABP were sedimented with the Triton-insoluble actin filaments.
The Effects of Biguanides on Thrombokinase, Thrombin and Trypsin
Authors: Roberts Phyllis S , Fleming Patricia B
Published: July 2018

A purified preparation of bovine thrombokinase (activated Factor X) loses the ability to hydrolyze TAME (p-toluenesulfonyl-L-arginine methyl ester) when it is incubated at 37° in 0.25 M Tris. HCl buffer, pH 7.4 with lauroxypropyl biguanide, N1, N5-dimethyl, N1-lauroxypropyl biguanide, N1-p-chlorophenethyl, N5-phenethyl biguanide, or N1-methyl, N1-p-chlorobenzyl, N5-o,p-dichlorobenzyl biguanide. Activity is lost much more slowly when 0.15 M NaCl is also present. Lauroxypropyl biguanide is the most potent of the compounds tested, 0.22 mM causing thrombokinase to lose almost all of its activity in about 30 minutes at 37° in pH 7.4 buffered saline.

Topical bovine thrombin also loses activity when incubated with either of the lauroxypropyl biguanides but not with the diphenethyl or the dibenzyl compound. Instead, the latter biguanides accelerate thrombin’s hydrolysis of TAME. The percent acceleration is not affected or only slightly decreased by the presence of 0.15 M NaCl or KCl, and it is also unaffected by incubating the enzyme with the compounds in buffered saline for 4 to 120 minutes.

Purified bovine trypsin is stabilized by both lauroxypropyl and the diphenethyl biguanide when incubated at 37° in pH 7.4 buffered saline for the 60 minute test period but neither compound has any effect on its rate of hydrolysis of TAME.

It is postulated that the enzymes first react rapidly and reversibly with all of the test biguanides and, depending upon the enzyme and the substrate, the rate of hydrolysis of the substrate is unaffected, accelerated or inhibited. The lauroxypropyl biguanides also undergo a second, slower reaction with both thrombokinase and thrombin that produces loss of enzymatic activity. The dibenzyl and diphenethyl biguanides also undergo this second slow reaction with thrombokinase but not with thrombin, and none of the biguanides undergo this second reaction with trypsin.
The Influence of Beta-adrenergic Blockade upon Baseline Blood Coagulation and Fibrinolytic Activity and upon the Responses to Venous Occlusion
Authors: Butler M. J , Smith Muriel , Irving M. H , Gordon Y. B , Ratky S. M , Rivers J. W. P , Hawkey C
Published: July 2018

Twenty volunteers were assessed for baseline coagulation (Thrombelastography, Factor VIII and platelet count) and fibrinolytic (Euglobulin Lysis Time and Fibrin(ogen) Degradation Products) activity two hours after ingestion of 60 mgm propranolol or an identical placebo administered on a double blind basis. The responses of these parameters to a fifteen minute period of venous occlusion was also assessed.

Beta adrenergic blockade reduced baseline FDP titres but did not affect other parameters, nor the local response to venous occlusion. During occlusion no significant change in coagulation activity could be detected in the non-occluded arm, but a small but statistically significant shortening of ELT was observed. Since this effect was prevented by propranolol it is probably mediated through adrenergic mechanisms.

Adrenergic stimuli appear to influence episodes of coagulation and fibrinolysis during everyday activity, but do not contribute to baseline levels of coagulation or fibrinolytic function.
Purification and Some Properties of Urokinase
Authors: Ogawa Nobuhisa , Yamamoto Hiroshi , Katamine Tomoaki , Tajima Hideo
Published: July 2018

A method for efficient extraction of urokinase from human urine was established by using polyacrylonitrile synthetic fiber as an adsorbent. By a combination of this method and known methods for purification of proteins, such as gel filtration and ion-exchange chromatography, urokinase with a specific activity of 224,000 International Units per mg of protein was obtained.

This sample showed homogeneity by ultracentrifugation, moving-boundary electrophoresis at pH 4.8 and 9.0 and Polyacrylamide gel disc electrophoresis at pH 4.0, but was separated into five active fractions by isoelectric focusing and Polyacrylamide gel disc electrophoresis at pH 9.4. This sample showed a single precipitin line in double radial immunodiffusion and Immunoelectrophoresis using rabbit anti-urokinase serum. This precipitin line fused with that of the International Standard preparation of urokinase and its immunological identity was established.

The molecular weight of this sample was 33,000, agreeing with that of the International Standard preparation. Its optimal pH as a plasminogen activator was approximately 8.8.
Ristocetin in the Diagnosis of von Willebrand’s Disease: A Comparison of Rate and Percent of Aggregation with Levels of the Plasma Factor(s) Necessary for Ristocetin Aggregation
Authors: Dowling S. V , Muntz R. H , D’Souza S , Ekert H
Published: July 2018

Percent aggregation and the aggregation rate of platelet rich plasma (PRP) in response to ristocetin (1.75 mg/ml) were measured in 20 normals and 16 patients with von Willebrand’s disease (vWd), with and without the addition of acetylsalicylic acid (ASA). Percent aggregation did not clearly distinguish between normals and patients with vWd. Aggregation rate was normal in only 2 of 16 patients, and after incubation of PRP with ASA 1 of these 2 remained normal.

The corrective effect of dilutions of platelet poor plasma (PPP) on the ristocetin response of washed platelets (von Willebrand’s factor, vWf ) was measured in 21 normals and 12 patients with vWd. All patients with vWd had abnormal levels. There was a significant correlation between aggregation rate and vWf in patients with vWd but not in normals. Both tests appear to measure closely related defects, and the aggregation rate is as specific as the vWf level for the diagnosis of clinically affected patients.
Clinical Observations and their Relationship to Laboratory Findings in the Haemophilias
Authors: Rainsford S. G , Hall Angela
Published: July 2018

Continuous observations in school terms have been made on the frequency of spontaneous bleeding episodes in a group of adolescent boys suffering from haemophilia (39 cases), Christmas disease (9 cases), and von Willebrand’s disease (2 cases). The observations suggest that in haemophilia other factors, besides the deficient factor VIII, affect the bleeding frequency. In the two boys with von Willebrand’s disease, the lower level of factor VIII was associated with the milder symptoms; whereas in boys with Christmas disease clinical severity and laboratory results seemed to be correlated.
Clinical and Genetic Aspects of Glanzmann’s Thrombasthenia in Israel
Authors: Reichert Nira , Seligsohn Uri , Ramot Bracha
Published: July 2018

Twenty two patients (12 males and 10 females) from all over Israel fulfilled the ‘Criteria for establishing the diagnosis of Glanzmann’s thrombasthenia. All have been observed to have a severe bleeding tendency since infancy or early childhood. In 8 out of 10 adult patients (7 females and 3 males) the bleeding manifestations have persisted over the years. In 2 adult patients major surgery was performed under platelet transfusions which appeared to prevent excessive bleeding. Pedigree analysis was possible for 21 patients who belong to 13 unrelated kindreds. Twelve kindreds are Jewish and one is Arab. Eleven of the 12 Jewish kindreds belong to the Iraqi Jewish community. Analysis of 16 sibships disclosed a corrected segregation ratio of 0.2, which is compatible with an autosomal recessive mode of inheritance. No bleeding manifestation whatsoever were observed in 30 obligatory carriers of thrombasthenia, and the haemostatic functions tested in 12 of them were entirely normal.
Impact of atmospheric stability on X-band and C-band synthetic aperture radar imagery of offshore windpark wakes
Authors: Djath B. , Schulz-Stellenfleth J. , Cañadillas B.
Published: July 2018

C-band and X-band Synthetic Aperture Radar (SAR) data acquired by the Sentinel-1 and TerraSAR-X satellites are used to study atmospheric wakes behind offshore wind parks in the German Bight. A particular focus is on the impact of atmospheric stability on wake parameters like the wake length. Stability parameters are estimated from measurements taken at the FINO-1 observation platform. Based on a data set covering different seasons and concentrating on the first German offshore wind park Alpha Ventus (AV), it is shown that in this area stable atmospheric conditions favour longer wakes. This is first demonstrated for situations, where the wake behind AV was unperturbed by other neighbor wind parks. In this case, wakes of more than 30 km length are observed. In a second step, the more complicated situation with wake superposition from different neighboring wind parks is analysed. It is shown that in this case, the merged wakes can extend to more than 70 km downstream.The analysis is challenged by two factors. First of all, the FINO-1 platform is within the wind farm wakes for a certain range of wind directions. This means stability estimates for the upstream conditions are not straightforward to obtain in these conditions. The second complication is associated with an apparent increase in the radar cross section downstream of wind parks observed on many SAR scenes, typically within the first 10 km downstream the wind park. A semi-empirical model is proposed to explain this effect by an increased downward momentum flux associated with increased turbulence generated by the wind park. Applying numerical inversion methods, a couple of typical downstream wind speed profiles are reproduced with this model based on SAR derived estimates of the friction velocity.
Laser-to-droplet alignment sensitivity relevant for laser-produced plasma sources of extreme ultraviolet light
Authors: Reijers Sten A. , Kurilovich Dmitry , Torretti Francesco , Gelderblom Hanneke , Versolato Oscar O.
Published: July 2018

We present and experimentally validate a model describing the sensitivity of the tilt angle, expansion, and the propulsion velocity of a tin micro-droplet irradiated by a 1 μm Nd:YAG laser pulse to its relative alignment. This sensitivity is particularly relevant in industrial plasma sources of extreme ultraviolet light for nanolithographic applications. Our model has but a single parameter: the dimensionless ratio of the laser spot size to the effective size of the droplet, which is related to the position of the plasma critical density surface. Our model enables the development of straightforward scaling arguments, in turn enabling precise control of the alignment sensitivity.
Re doping induced 2H-1T phase transformation and ferromagnetism in MoS2 nanosheets
Authors: Xia Baorui , Liu Peitao , Liu Yonggang , Gao Daqiang , Xue Desheng , Ding Jun
Published: July 2018

In this paper, Re-doped MoS2 nanosheets were synthesized by a facile hydrothermal reaction and an annealing process. Through structural characterization, it was observed that the doping of Re could lead to 2H-1T transformation in both the Re and Mo coordinating structures, and the 1T ratios of Mo and Re atoms increased with the Re-doping concentration. Hysteresis loops demonstrated intrinsic room temperature ferromagnetism in the Re-doped MoS2 nanosheets, and the value of saturated magnetization reached 8 memu/g when the doping concentration of Re was 17.12 at. %. The magnetic properties resulted from the increasing net magnetic moments of Re atoms and 1T-coordinated Mo atoms. Additionally, the 1T-incorporated 2H structure and magnetism were thermally stable in these samples. These results explored a new path for MoS2 nanosheets to be applied in spintronic devices in the future.
Piezoelectric graphene field effect transistor pressure sensors for tactile sensing
Authors: Yogeswaran N. , Navaraj W. T. , Gupta S. , Liu F. , Vinciguerra V. , Lorenzelli L. , Dahiya R.
Published: July 2018

This paper presents graphene field-effect transistor (GFET) based pressure sensors for tactile sensing. The sensing device comprises GFET connected with a piezoelectric metal-insulator-metal (MIM) capacitor in an extended gate configuration. The application of pressure on MIM generates a piezo-potential which modulates the channel current of GFET. The fabricated pressure sensor was tested over a range of 23.54–94.18 kPa, and it exhibits a sensitivity of 4.55 × 10−3 kPa−1. Further, the low voltage (∼100 mV) operation of the presented pressure sensors makes them ideal for wearable electronic applications.
Oscillating planar Hall response in bulk crystal of topological insulator Sn doped Bi1.1Sb0.9Te2S
Authors: Wu Bin , Pan Xing-Chen , Wu Wenkai , Fei Fucong , Chen Bo , Liu Qianqian , Bu Haijun , Cao Lu , Song Fengqi , Wang Baigeng
Published: July 2018

We report the low-temperature magneto-transport in the bulk-insulating single crystal of topological insulator Sn doped Bi1.1Sb0.9Te2S. Shubnikov-de Haas oscillations appear with their reciprocal frequency proportional to cos θ, demonstrating the dominant transport of topological surface states. While the magnetic field rotates on the sample surface, the planar Hall effect arises with sizeable oscillations following a relation of cos θ sin θ. Its amplitude reaches the maximum at the lowest temperature and drops to nearly zero at temperature higher than 100 K. All these evidences consolidate such planar Hall oscillations as another golden criterion on the topological surface transport.
Terahertz quantum cascade VECSEL with watt-level output power
Authors: Curwen Christopher A. , Reno John L. , Williams Benjamin S.
Published: July 2018

We report a terahertz quantum-cascade vertical-external-cavity surface-emitting laser (QC-VECSEL) whose output power is scaled up to watt-level by using an amplifying metasurface designed for increased power density. The metasurface is composed of a subwavelength array of metal-metal waveguide antenna-coupled sub-cavities loaded with a terahertz quantum-cascade gain material. Unlike previously demonstrated THz QC-VECSELs, the sub-cavities operate on their third-order lateral modal resonance (TM03), instead of their first-order (TM01) resonance. This results in a metasurface with a higher spatial density of the gain material, leading to an increased output power per metasurface area. In pulsed mode operation, peak THz output powers up to 830 mW at 77 K and 1.35 W at 6 K are observed, while a single-mode spectrum and a low divergence beam pattern are maintained. In addition, piezoelectric control of the cavity length allows approximately 50 GHz of continuous, single-mode tuning without a significant effect on output power or beam quality.
A pico-second resolution arbitrary timing generator based on time folding and time interpolating
Authors: Qin Xi , Zhang Wen-Zhe , Wang Lin , Tong Yu , Yang Heng , Rui Ying , Rong Xing , Du Jiang-Feng
Published: July 2018

We report a pico-second resolution arbitrary timing generator which is implemented with a field-programmable-gate-array. The arbitrary timing/pattern generator is based on a time folding method which is combined with a delay chain for fine time interpolating. The time folding method can not only break the limitation of sequence time resolution contributed by the minimum chain cell delay but also improve the chain linearity. The arbitrary timing generator which is based on the time folding technique is integrated in a printed-circuit board, and a 5 ps time resolution with enhanced output linearity is obtained. The dynamic range of output pulses from the arbitrary timing generator is from 5 ns to 10 s. In this paper, we describe the principle, the circuit design, and the characterizations of the arbitrary timing generator. We also discuss the improvement of performance in timing generation using the time folding method. The high-performance arbitrary timing generator has a bright future to be used in the applications that require high-resolution timing sequence generation.
Ab Initio and DFT Study on Cyclophosphamide: Anticancer and Immunomodulating Agents
Authors: Bruno Giuseppe
Published: July 2018

Cyclophosphamide is presently the most frequently used drug for antineoplastic chemotherapy. It has shown a great response in the treatment of human malignancies including leukemia, lymphoma, germ cell tumours, medulloblastomas, and carcinomas of the breast, lung, and cervix. Cyclophosphamide is also one of the most important immunosuppressive agents. This study investigates the quantum-chemical electronic properties of cyclophosphamide, as well as some of its metabolites, which are computed using ab-initio and DFT calculations. The interaction energy calculations between water molecules and the cyclophosphamide show how, in the solid state, the presence of water of crystallisation will make cyclophosphamide more stable over time. Atomic charges, dipole moment, frontier molecular orbitals, electrostatic potential isosurface, geometric parameters, and proton affinity on every nitrogen site enable the characterisation of the electronic properties and clearly illustrate the reactive sites that could be associated with this biologically important class of molecules.
Simulation of fuel bed ignition by wildland firebrands
Authors: Matvienko O. V. , Kasymov D. P. , Filkov A. I. , Daneyko O. I. , Gorbatov D. A.
Published: July 2018

A 3-D mathematical model of fuel bed (FB) ignition initiated by glowing firebrands originating during wildland fires is proposed. In order to test and verify the model, a series of experiments was conducted to determine the FB ignition time by a single pine bark and twig firebrand (Pinus sylvestris). Irrespective of the pine bark sample sizes and experimental conditions, the ignition of the FB was not observed. Conversely, pine twigs, under certain parameters, ignited the FB in the range of densities (60–105 kg m−3) and with the airflow velocity of ≥2 m s−1. The results of the mathematical modelling have shown that a single pine bark firebrand ≤5 cm long with a temperature of T ≤ 1073 K does not ignite in the flaming mode the FB, and only the thermal energy of larger particles is sufficient for flaming ignition of the adjacent layers of the FB. The analysis of the results has shown that the firebrand length is a major factor in the initiation of ignition. Comparison of the calculated and observed FB ignition times by a single firebrand have shown that our modelling accords well with the experimental results.
Identification of a new subset of lymph node stromal cells involved in regulating plasma cell homeostasis
Authors: Huang Hsin-Ying , Rivas-Caicedo Ana , Renevey François , Cannelle Hélène , Peranzoni Elisa , Scarpellino Leonardo , Hardie Debbie L. , Pommier Arnaud , Schaeuble Karin , Favre Stéphanie , Vogt Tobias K. , Arenzana-Seisdedos Fernando , Schneider Pascal , Buckley Christopher D. , Donnadieu Emmanuel , Luther Sanjiv A.
Published: July 2018

Significance

Lymph nodes (LNs) are sites where adaptive immunity is initiated, leading to the generation of plasma cells (PCs) secreting large amounts of antibodies that typically interfere with pathogen spread. PCs are known to depend on extrinsic factors provided by niche cells to stay alive; however, the critical niche cells are still poorly understood. Here we present evidence for a fibroblast subset within murine and human LNs that is unique to the medulla where PCs reside. These fibroblasts produce factors that positively regulate PC homeostasis, similar to macrophages. Knowing the critical niche cells may help to design intervention strategies to target this niche in the setting of autoimmune disease caused by PCs secreting autoreactive antibodies.
Lifelong CMV infection improves immune defense in old mice by broadening the mobilized TCR repertoire against third-party infection
Authors: Smithey Megan J. , Venturi Vanessa , Davenport Miles P. , Buntzman Adam S. , Vincent Benjamin G. , Frelinger Jeffrey A. , Nikolich-Žugich Janko
Published: July 2018

Significance

Epidemiological studies have shown a correlation between CMV infection and immune system aging, especially in elderly populations. It remains unclear whether CMV infection is a key driver of, or simply a factor associated with, aging of the immune system. We show that aging in the presence of lifelong CMV infection improves T cell immunity in old animals by broadening the immune response to a different pathogen. Animals that have aged with CMV are able to recruit novel T cells into these immune responses that are present in, but not utilized in, animals aging without CMV. These data squarely challenge the premise that CMV is solely detrimental to the aging of the adaptive immune system.
Host quality induces phenotypic plasticity in a wing polyphenic insect
Authors: Lin Xinda , Xu Yili , Jiang Jianru , Lavine Mark , Lavine Laura Corley
Published: July 2018

Significance

Variation in food nutrient content and density are key ecological factors linked to the expression of condition-dependent, adaptive phenotypes such as wing polyphenisms. There is very little known about exactly what the ecological cue is that induces the appropriate insect phenotype in wing polyphenic insects. Our study reveals that glucose concentration of the host plant and insect density directly influence the development of brown planthoppers into either the long-winged migratory morph or the short-winged reproductive morph. This study is a step in linking host quality signals and other factors such as density to the induction of adaptive phenotypes in insects.
Plant height and hydraulic vulnerability to drought and cold
Authors: Olson Mark E. , Soriano Diana , Rosell Julieta A. , Anfodillo Tommaso , Donoghue Michael J. , Edwards Erika J. , León-Gómez Calixto , Dawson Todd , Camarero Martínez J. Julio , Castorena Matiss , Echeverría Alberto , Espinosa Carlos I. , Fajardo Alex , Gazol Antonio , Isnard Sandrine , Lima Rivete S. , Marcati Carmen R. , Méndez-Alonzo Rodrigo
Published: July 2018

Significance

As trees worldwide experience mortality or dieback with increasing drought and low tundras grow taller with warming, understanding the link between plant height and climate is increasingly important. We show that taller plants have predictably wider water-conducting conduits, and that wider conduits within species are more vulnerable to conduction-blocking embolisms. These two observations suggest that tall plants in formerly moist areas die because their wide conduits are excessively vulnerable under novel drought conditions. Also, the cold that limits conduit diameter, and therefore height, in tundra plants is relaxed under warming, permitting wider conduits and taller plants. That plant height appears linked to climate via plant hydraulics helps explain why vegetation height differs across biomes and is altering with climate change.
First evidence for silica condensation within the solar protoplanetary disk
Authors: Komatsu Mutsumi , Fagan Timothy J. , Krot Alexander N. , Nagashima Kazuhide , Petaev Michail I. , Kimura Makoto , Yamaguchi Akira
Published: July 2018

Significance

The oldest solar system solids dated are refractory inclusions [Ca-Al–rich inclusions (CAIs) and amoeboid olivine aggregates (AOAs)], which occur in chondritic meteorites and provide records of high-temperature processes in the early solar system. An ultrarefractory CAI and the silica-phase quartz occur in an AOA from the carbonaceous chondrite Yamato-793261, indicating formation over a temperature range exceeding 650 K. The minerals have
16
O-rich compositions consistent with the nebular setting associated with refractory inclusions. This AOA provides direct evidence that silica condensed from gas in a CAI/AOA-forming region in our solar system indicates that gas became Si-rich as Mg condensed and may explain the origin of silica detected from infrared spectroscopy of T Tauri and asymptotic giant branch stars.
Ancient human parvovirus B19 in Eurasia reveals its long-term association with humans
Authors: Mühlemann Barbara , Margaryan Ashot , Damgaard Peter de Barros , Allentoft Morten E. , Vinner Lasse , Hansen Anders J. , Weber Andrzej , Bazaliiskii Vladimir I. , Molak Martyna , Arneborg Jette , Bogdanowicz Wieslaw , Falys Ceri , Sablin Mikhail , Smrčka Václav , Sten Sabine , Tashbaeva Kadicha , Lynnerup Niels , Sikora Martin , Smith Derek J. , Fouchier Ron A. M. , Drosten Christian , Sjögren Karl-Göran , Kristiansen Kristian , Willerslev Eske , Jones Terry C.
Published: July 2018

Significance

The majority of viral genomic sequences available today are fewer than 50 years old. Parvovirus B19 (B19V) is a ubiquitous human pathogen causing fifth disease in children, as well as other conditions. By isolating B19V DNA from human remains between ∼0.5 and 6.9 thousand years old, we show that B19V has been associated with humans for thousands of years, which is significantly longer than previously thought. We also show that the virus has been evolving at a rate an order of magnitude lower than estimated previously. Access to viral sequences isolated from individuals living thousands of years ago greatly improves our understanding of the timescales of virus evolution, spatiotemporal distribution, and their substitution rates, and can uncover genetic diversity that is now extinct.
Antimalarial proteasome inhibitor reveals collateral sensitivity from intersubunit interactions and fitness cost of resistance
Authors: Kirkman Laura A. , Zhan Wenhu , Visone Joseph , Dziedziech Alexis , Singh Pradeep K. , Fan Hao , Tong Xinran , Bruzual Igor , Hara Ryoma , Kawasaki Masanori , Imaeda Toshihiro , Okamoto Rei , Sato Kenjiro , Michino Mayako , Alvaro Elena Fernandez , Guiang Liselle F. , Sanz Laura , Mota Daniel J. , Govindasamy Kavitha , Wang Rong , Ling Yan , Tumwebaze Patrick K. , Sukenick George , Shi Lei , Vendome Jeremie , Bhanot Purnima , Rosenthal Philip J. , Aso Kazuyoshi , Foley Michael A. , Cooper Roland A. , Kafsack Bjorn , Doggett J. Stone , Nathan Carl F. , Lin Gang
Published: July 2018

Significance

Protozoal proteasome is a validated target for antimalarial drug development, but species selectivity of reported inhibitors is suboptimal. Here we identify inhibitors with improved selectivity for malaria proteasome β5 subunit over each active subunit of human proteasomes. These compounds kill the parasite in each stage of its life cycle. They interact synergistically with a β2 inhibitor and with artemisinin. Resistance to the β5 inhibitor arose through a point mutation in the nonproteolytic β6 subunit. The same mutation made the mutant strain more sensitive to a β2 inhibitor and less fit to withstand irradiation. These findings reveal complex interplay among proteasome subunits and introduce the prospect that combined inhibition of β2 and β5 subunits can afford synergy and thwart resistance.
Molecular profiling of reticular gigantocellularis neurons indicates that eNOS modulates environmentally dependent levels of arousal
Authors: Tabansky Inna , Liang Yupu , Frankfurt Maya , Daniels Martin A. , Harrigan Matthew , Stern Sarah , Milner Teresa A. , Leshan Rebecca , Rama Rrezarta , Moll Tabea , Friedman Jeffrey M. , Stern Joel N. H. , Pfaff Donald W.
Published: July 2018

Significance

Certain large neurons deep in the brainstem, in the nucleus gigantocellularis (NGC), are crucial for waking up the brain from deep sleep, anesthesia, or injury. NGC neurons, which project axons to central thalamus, should be especially important because central thalamic stimulation heightens CNS arousal in animals and in human patients. We have used the retroTRAP technique to discover mRNAs enriched in such NGC neurons. One mRNA, for endothelial nitric oxide synthase (eNOS), is uniquely expressed. By experiments both on the environmental/sensory side and with respect to motoric regulation, endothelial nitric oxide expression is shown to be functionally important. Five independent lines of evidence indicate that these eNOS neurons have a significant relation with their blood supply.
Disruption of divisome assembly rescued by FtsN–FtsA interaction in
Escherichia coli
Authors: Pichoff Sebastien , Du Shishen , Lutkenhaus Joe
Published: July 2018

Significance

Cell division in
Escherichia coli
requires 12 essential proteins that assemble into the divisome in a sequential manner. Assembly starts with formation of the Z-ring and culminates with the arrival of FtsN, which triggers septal peptidoglycan synthesis. Normally, deletion of any of these 12 proteins disrupts divisome assembly and results in a division block. However, about half of these proteins can be bypassed under some conditions, raising a question of how the divisome assembles under such conditions. Here we show that these bypasses require the interaction of FtsA with FtsN and that this normally weak interaction is enhanced under these conditions, leading to the back-recruitment of the other divisome proteins to the Z-ring.
Othering the West in the online Jihadist propaganda magazines Inspire and Dabiq
Authors: Lorenzo-Dus Nuria , Macdonald Stuart
Published: July 2018

This paper examines how the jihadist terrorist groups Al Qaeda and the so-called Islamic State discursively construct ‘the West’ as an alien, aberrant ‘other’ in their respective online propaganda magazines Inspire and Dabiq over a 5 year period (2010–2015). The analysis integrates insights from the field of Terrorism Studies into a Corpus Assisted Discourse Studies approach, working centrally with the notions of othering and conventionalised impoliteness. Our findings reveal not only that othering is a key discursive process in the groups’ online propaganda machinery but that it is discursively realised via homogenisation, suppression (stereotyping) and pejoration strategies. The latter are further examined via the notion of conventional impoliteness. Pointed criticism emerges as the most frequent conventionalised impoliteness strategy in both magazines. Threats, condescension and exclusion strategies are also saliently used, albeit with different relative frequencies within each magazine. The findings show the value of Discourse Analysis to research into (jihadist) terrorism, including the possibility of drawing upon its findings to develop tailored counter-messages to those advanced by (jihadist) terrorist groups.
Transsexual Attractions and Sexual Reassignment Surgery: Risks and Potential Risks
Authors: Fitzgibbons Richard P.
Published: July 2018

Transsexual issues and sexual reassignment surgery (SRS) are receiving a great deal of attention and support in the media, schools, and government. Given the early age at which youth seek treatment for transsexual attractions (TSA) and gender dysphoria and given the serious risks associated with such treatment, it is essential that family and youth be advised about these risks and alternative treatment options. Physicians and mental-health professionals have a professional responsibility to know and communicate the serious risks, in particular risk of suicide, that are associated with SRS; the spontaneous resolution of TSA in youth; the psychological conflicts that have been identified in such patients and in their parents; the successful treatment of conflicts associated TSA and the regrets of those who have been through SRS. SRS and gender theory are also viewed from the faith perspective of Pope Francis and Pope Emeritus Benedict XVI.

Lay summary: Transsexuals and sex-change operations are receiving a great deal of attention. Young people may seek treatment for transsexual attractions at an early age even though these attractions may go away on their own. Psychological conflicts have been identified in these patients and their parents and may be successfully treated. There are serious risks associated with sex change. They include the risk of depressive illness and suicide. Physicians and mental-health professionals should know these risks and the regrets of those who have been through sex-change operations. These patients and their families also should be informed of other treatment options.
Predicting radial-velocity jitter induced by stellar oscillations based on Kepler data
Authors: Yu Jie , Huber Daniel , Bedding Timothy R , Stello Dennis
Published: July 2018

Radial-velocity jitter due to intrinsic stellar variability introduces challenges when characterizing exoplanet systems, particularly when studying small (sub-Neptune-sized) planets orbiting solar-type stars. In this letter we predicted for dwarfs and giants the jitter due to stellar oscillations, which in velocity have much larger amplitudes than noise introduced by granulation. We then fitted the jitter in terms of the following sets of stellar parameters: (1) Luminosity, mass, and effective temperature: the fit returns precisions (i.e. standard deviations of fractional residuals) of 17.9  and 27.1  per  cent for dwarfs and giants, respectively. (2) Luminosity, effective temperature, and surface gravity: the precisions are the same as using the previous parameter set. (3) Surface gravity and effective temperature: we obtain a precision of 22.6  per  cent for dwarfs and 27.1  per  cent for giants. (4) Luminosity and effective temperature: the precision is 47.8  per  cent for dwarfs and 27.5  per  cent for giants. Our method will be valuable for anticipating the radial-velocity stellar noise level of exoplanet host stars to be found by the TESS and PLATO space missions, and thus can be useful for their follow-up spectroscopic observations. We provide publicly available code (https://github.com/Jieyu126/Jitter) to set a prior for the jitter term as a component when modelling the Keplerian orbits of the exoplanets.
Circadian variation in pulmonary inflammatory responses is independent of rhythmic glucocorticoid signaling in airway epithelial cells
Authors: Ince Louise M. , Zhang Zhenguang , Beesley Stephen , Vonslow Ryan M. , Saer Ben R. , Matthews Laura C. , Begley Nicola , Gibbs Julie E. , Ray W. David , Loudon S. I. Andrew
Published: July 2018

The circadian clock is a critical regulator of immune function. We recently highlighted a role for the circadian clock in a mouse model of pulmonary inflammation. The epithelial clock protein Bmal1 was required to regulate neutrophil recruitment in response to inflammatory challenge. Bmal1 regulated glucocorticoid receptor (GR) recruitment to the neutrophil chemokine, CXC chemokine ligand 5 (CXCL5), providing a candidate mechanism. We now show that clock control of pulmonary neutrophilia persists without rhythmic glucocorticoid availability. Epithelial GR‐null mice had elevated expression of proinflammatory chemokines in the lung under homeostatic conditions. However, deletion of GR in the bronchial epithelium blocked rhythmic CXCL5 production, identifying GR as required to confer circadian control to CXCL5. Surprisingly, rhythmic pulmonary neutrophilia persisted, despite nonrhythmic CXCL5 responses, indicating additional circadian control mechanisms. Deletion of GR in myeloid cells alone did not prevent circadian variation in pulmonary neutrophilia and showed reduced neutrophilic inflammation in response to dexamethasone treatment. These new data show GR is required to confer circadian control to some inflammatory chemokines, but that this alone is insufficient to prevent circadian control of neutrophilic inflammation in response to inhaled LPS, with additional control mechanisms arising in the myeloid cell lineage.—Ince, L. M., Zhang, Z., Beesley, S., Vonslow, R. M., Saer, B. R., Matthews, L. C., Begley, N., Gibbs, J. E., Ray, D. W., Loudon, A. S. I. Circadian variation in pulmonary inflammatory responses is independent of rhythmic glucocorticoid signaling in airway epithelial cells. FASEB J. 33, 126–139 (2019).www.fasebj.org
Dexmedetomidine Preconditioning Ameliorates Inflammation and Blood–Spinal Cord Barrier Damage After Spinal Cord Ischemia-Reperfusion Injury by Down-Regulation High Mobility Group Box 1-Toll-Like Receptor 4-Nuclear Factor κB Signaling Pathway
Authors: Liu Jiao , Zhang Shuangshuang , Fan Xiaona , Yuan Fen , Dai Jun , Hu Ji
Published: July 2018

Study Design.

To evaluate the effect of Dexmedetomidine (Dex) on the inflammatory response and the integrity of blood–spinal cord barrier (BSCB) after spinal cord ischemia-reperfusion injury (SCIRI).

Objective.

To investigate the role of Dex in spinal cord I/R, particularly in the high mobility group box 1-toll-like receptor 4-nuclear factor κB (HMGB1-TLR4-NF-κB) pathway and the integrity of BSCB.

Summary of Background Data.

High mobility group box 1 (HMGB1) has been identified as a key mediator for the inflammatory response after spinal cord injury. Toll-like receptor 4-nuclear factor κB (TLR4-NF-κB) signaling pathway is the downstream of HMGB1. Dex preconditioning could protect the spinal cord from I/R injury by inhibiting HMGB1 and stabilizing the integrity of BSCB. But its underlying mechanism is not fully understood.

Methods.

Forty-eight male Japanese white rabbits were randomly assigned to three groups (16 rabbits/group): sham, I/R, and Dex + I/R. The hind-limb motor function was assessed at 12 hours intervals for 48 hours after reperfusion using the modified Tarlov scale score. The expression of HMGB1, TLR4, NF-κB, and tumor necrosis factor α (TNF-α) was evaluated by real-time polymerase chain reaction (RT-PCR) and Western blot. The permeability of BSCB was examined via Evans blue (EB) extravasation.

Results.

Compared with sham group, spinal cord I/R increased the expression of HMGB1, TLR4, NF-κB, and TNF-α as well as the permeability of BSCB (P < 0.05). Spinal cord I/R induced the decline of the score of hind-limb motor function (P < 0.01). Preconditioning with Dex attenuated the up-regulation of the express of HMGB1, TLR4, NF-κB, TNF-α, and stabilized the permeability of BSCB (P < 0.05). Dex preconditioning also improved the hiatopathological outcome and the motor function (P < 0.01).

Conclusion.

Dex preconditioning may inhibit the inflammatory response and stabilize the integrity of BSCB at least partially by inhibiting the HMGB1-TLR4-NF-κB signaling pathway to protect spinal cord from ischemia/reperfusion injury.

Level of Evidence: 2
Triceps Repair and Restoration of Triceps Footprint With Anchorless Suture Fixation
Authors: Steffes Matthew , Tayne Samantha , Osmani Feroz , Edwards Gary , MacGillis Kyle , Kim Walter , Hammarstedt Jon E. , Goldberg Benjamin
Published: July 2018

Triceps tendon rupture is an uncommon yet potentially devastating injury affecting patients over a broad demographic. Surgical treatment is essential to restore upper extremity functional status, and a vast array of techniques has been implemented with different fixation devices including suture buttons, intraosseous anchors, and suture repairs. Outcomes of distal triceps tendon repair have demonstrated nearly full return of functional capacity. Complications include infection, ulnar nerve neuropathy, arthrofibrosis, flexion contracture, hardware irritation, and most commonly, repair failure. We illustrate a triceps repair technique with suture fixation that restores the tendinous footprint without need of an adjunctive device.
The impact of the built environment on health behaviours and disease transmission in social systems
Authors: Pinter-Wollman Noa , Jelić Andrea , Wells Nancy M.
Published: July 2018

The environment plays an important role in disease dynamics and in determining the health of individuals. Specifically, the built environment has a large impact on the prevention and containment of both chronic and infectious disease in humans and in non-human animals. The effects of the built environment on health can be direct, for example, by influencing environmental quality, or indirect by influencing behaviours that impact disease transmission and health. Furthermore, these impacts can happen at many scales, from the individual to the society, and from the design of the plates we eat from to the design of cities. In this paper, we review the ways that the built environment affects both the prevention and the containment of chronic and infectious disease. We bring examples from both human and animal societies and attempt to identify parallels and gaps between the study of humans and animals that can be capitalized on to advance the scope and perspective of research in each respective field. By consolidating this literature, we hope to highlight the importance of built structures in determining the complex dynamics of disease and in impacting the health behaviours of both humans and animals.

This article is part of the theme issue ‘Interdisciplinary approaches for uncovering the impacts of architecture on collective behaviour’.
Plant aquaporins: the origin of NIPs
Authors: Borstlap Adrianus C.
Published: July 2018

Many of the aquaporin genes in Cyanobacteria belong to the AqpN-clade. This clade was also the cradle of plant NIPs (nodulin-26 like intrinsic proteins) whose members are transporters for glycerol and several hydroxylated metalloids. The superphylum of Archaeplastida acquired the primordial NIP-gene most likely from the cyanobacterium that, some 1500 million years ago, became the ancestor of all plastids.
Regulation of gene drive expression increases invasive potential and mitigates resistance
Authors: Hammond Andrew , Karlsson Xenia , Morianou Ioanna , Kyrou Kyros , Beaghton Andrea , Gribble Matthew , Kranjc Nace , Galizi Roberto , Burt Austin , Crisanti Andrea , Nolan Tony
Published: July 2018

CRISPR-Cas9 nuclease-based gene drives rely on inducing chromosomal breaks in the germline that are repaired in ways that lead to a biased inheritance of the drive. Gene drives designed to impair female fertility can suppress populations of the mosquito vector of malaria. However, strong unintended fitness costs, due to ectopic nuclease expression, and high levels of resistant mutations, limited the potential of the first generation of gene drives to spread.

Here we show that changes to regulatory sequences in the drive element, designed to contain nuclease expression to the germline, confer improved fecundity over previous versions and generate drastically lower rates of target site resistance. We employed a genetic screen to show that this effect is explained by reduced rates of end-joining repair of DNA breaks at the target site caused by deposited nuclease in the embryo.

Highlighting the impact of deposited Cas9, many of the mutations arising from this source of nuclease activity in the embryo are heritable, thereby having the potential to generate resistant target sites that reduce the penetrance of the gene drive.

Finally, in cage invasion experiments these gene drives show improved invasion dynamics compared to first generation drives, resulting in greater than 90% suppression of the reproductive output and a delay in the emergence of target site resistance, even at a resistance-prone target sequence. We shed light on the dynamics of generation and selection of resistant alleles in a population by tracking, longitudinally, the frequency of resistant alleles in the face of an invading gene drive. Our results illustrate important considerations for future gene drive design and should expedite the development of gene drives robust to resistance.
Adjusting for systematic technical biases in risk assessment of gene signatures in transcriptomic cancer cohorts
Authors: Mestres Adrià Caballé , Llergo Antonio Berenguer , Attolini Camille Stephan-Otto
Published: July 2018

In recent years, many efforts in clinical and basic research have focused on finding molecular features of tumor samples with prognostic or classification potential. Among these, the association of the expression of gene signatures with survival probability is of special interest given its relatively direct applicability in the clinic and its power to shed insights into the molecular basis of cancer.

Although great efforts have been invested in data processing to control for unknown sources of variability in a gene-wise manner, little is known about the behaviour of gene signatures with respect to the effect of technical variables.

Here we show that the association of signatures with survival may be biased due to technical reasons and propose a simple and low intensive methodology based on correction by expectation under gene randomization. The resulting estimates are centred around zero and ensure correct asymptotic inference. Moreover, our methodology is robust against spurious correlations between global dataset tendencies and clinical outcome.

All tools (will be soon) available in the "HRunbiased" R package as well as processed datasets for colorectal and breast cancer.