bluuebunny/crossref_metadata_2025 huggingface dataset:
Transient setting of relativistic ponderomotive non-linearity and filamentation of ultra-short laser pulses in collisionless plasmas
Authors: Sharma R.P. , Kumar Narender , Uma R. , Singh Ram Kishor , Gupta P.K.
Published: July 2019

We study the setting up of relativistic ponderomotive non-linearity in an under-dense collisionless cold plasma. Using the fluid model, coupled system of equations of the laser beam and electron plasma oscillations has been derived. We present the numerical simulation for this coupled system of equations, when the coupling arises through relativistic ponderomotive non-linearity. The filamentation of the laser beam has been found to vary appreciably with perturbation wave number. The results show that with time, localized structures become more complex and the plasma oscillation frequency spectra have several harmonic peaks at terahertz frequencies when the electron plasma frequency is in terahertz range and laser frequency is around 2.35 × 1015 rad/s. We also present the semi-analytical model to capture the underlying physics.
Leaving No One Behind: Participatory Technology Appraisal as a Platform for Agenda Setting to Address Disparities in Access to Health Services in Thailand
Authors: Tantivess Sripen , Doungthipsirikul Suradech
Published: July 2019

Objectives

This article discusses how participatory technology appraisal as part of the Universal Coverage Scheme (UCS) in Thailand contributes to improving access to essential health services among vulnerable populations.

Methods

Document review was conducted on health technology appraisal approaches introduced by the UCS. The review involves health benefit proposals advanced by stakeholders and also meeting minutes of relevant working groups and committees published between 2010 and 2015.

Results

From the establishment of the UCS participatory technology appraisal mechanism in 2010 until 2015, a total of 133 health interventions have been nominated. Some nominations highlight problems in access to care among vulnerable populations. As policy advocates continue to be involved in the latter stages of coverage decisions, they have opportunities to persuade policy makers and other stakeholders to agree to the rationales of their proposals. Some interventions were rejected because they did not meet value for money, affordability, and feasibility criteria; however, topic nominations from stakeholders as well as relevant deliberation throughout the technology appraisal processes have a potential to improve accessibility of health care among the disadvantaged.

Conclusions

Through participation in the UCS policy-making processes, key stakeholders are able to direct the attention of decision makers to significant gaps in access to services among vulnerable citizens, a health system problem rarely brought to discussion by policy elites and experts. The Thai experience reaffirms participatory technology appraisal as a supportive measure to providing universal health coverage.
New insights into the species diversity of Bartramia Hedw. (Bryophyta) in Antarctica
Authors: Câmara Paulo E.A.S. , Soares Abel E.R. , Henriques Diego Knop , Peralta Denilson Fernandes , Bordin Juçara , Carvalho-Silva Micheline , Stech Michael
Published: July 2019

In Antarctica, the genus Bartramia has been restricted to a single polymorphic species, B. patens. Its status as a separate species or a subspecies of the Northern Hemisphere B. ithyphylla was debated. In the present paper, we combine analyses of chloroplast (trnS–rps4–trnT–trnL–trnF region) and nuclear ITS sequences with a reinvestigation of morphological characteristics to infer the identity of Antarctic Bartramia. Phylogenetic and Automatic Barcode Gap Discovery (ABGD) species delimitation analyses indicate that the species diversity of Bartramia in Antarctica has been underestimated, since two species were identified, both belonging to Bartramia sect. Pyridium. Of these, B. subsymmetrica is a new record of the species for Antarctica, as it has previously only been recorded from Livingston Island, South Shetlands. The other species is B. patens, which is separated from B. ithyphylla by newly inferred morphological characteristics and is a sister species to the latter in the molecular phylogenetic analyses. Consequently, we consider B. ithyphylla to be a Northern Hemisphere instead of a bipolar species. The suggested conspecificity of both taxa into one species in the ABGD analysis is considered to result from overlumping by this species delimitation method. The delimitation of the three species of section Bartramia (B. halleriana, B. mossmaniana and B. pomiformis) and the circumscription of the genus Bartramia are discussed.
MARSWRF Prediction of Entry Descent Landing Profiles: Applications to Mars Exploration
Authors: Fonseca Ricardo Morais , Zorzano María‐Paz , Martín‐Torres Javier
Published: July 2019

In this paper we use the Mars implementation of the Planet Weather Research and Forecasting model, MarsWRF, to simulate the Entry, Descent and Landing (EDL) vertical profiles from six past missions: Pathfinder, Mars Exploration Rovers Opportunity and Spirit, Phoenix, Mars Science Laboratory Curiosity rover, and ExoMars 2016 (Schiaparelli), and compare the results with observed data. In order to investigate the sensitivity of the model predictions to the atmospheric dust distribution, MarsWRF is run with two prescribed dust scenarios. It is concluded that the MarsWRF EDL predictions can be used for guidance into the design and planning stage of future missions to the planet, as it generally captures the observed EDL profiles, although it has a tendency to underestimate the temperature and overestimate the density for heights above 15 km. This could be attributed to an incorrect representation of the observed dust loading. We have used the model to predict the EDL conditions that may be encountered by two future missions: ExoMars 2020 and Mars 2020. When run for Oxia Planum and Jezero Crater for the expected landing time, MarsWRF predicts a large sensitivity to the dust loading in particular for the horizontal wind speed above 10‐15 km with maximum differences of up to ±30 m/s for the former and ±15 m/s for the latter site. For both sites, the best time for EDL, that is, when the wind speed is generally the weakest with smaller shifts in direction, is predicted to be in the late morning and early afternoon.
ScintPi: A Low‐Cost, Easy‐to‐Build GPS Ionospheric Scintillation Monitor for DASI Studies of Space Weather, Education, and Citizen Science Initiatives
Authors: Rodrigues F. S. , Moraes A. O.
Published: July 2019

We report the proposal and results of a low‐cost, easy‐to‐build GPS‐based sensor for detection and monitoring ionospheric irregularities through the detection of amplitude scintillation. The system is based on the Raspberry Pi single‐board computer combined with an Adafruit Ultimate GPS peripheral, which is capable of measuring (at 10‐Hz rate) the intensity of the L1 signals transmitted by GPS satellites. We introduce and discuss results of short‐ and long‐term observations obtained with a prototype of this system deployed in Presidente Prudente, a low magnetic latitude site in Brazil. The deployment and observations were carried out to test the ability of the system to detect ionospheric scintillations and, therefore, monitor the occurrence of ionospheric irregularities associated with equatorial spread F. Our results show that this low‐cost sensor is indeed capable of detecting scintillation events associated with equatorial spread F. Comparison with simultaneous, collocated measurements made by a commercial scintillation monitor are also presented. The joint observations allowed us to quantify the performance of the low‐cost monitor and to identify sources of potential limitations. While the sensor cannot (and it was not intended to) substitute commercial scintillation monitors, the low cost allows its use in studies of ionospheric irregularities (space weather) that require observations made by distributed arrays of small instruments (DASI). Furthermore, the simplicity of the sensor design stimulates its use in educational and citizen science initiatives.
The Influence of Water on the Strength of Olivine Dislocation Slip Systems
Authors: Tielke Jacob , Mecklenburgh Julian , Mariani Elisabetta , Wheeler John
Published: July 2019

The nature of lattice‐preferred orientation (LPO) in olivine‐rich rocks strongly influences many important physical properties of Earth's upper mantle. Different LPO types have been observed to develop in deformation experiments on olivine‐rich rocks carried out at different water fugacity conditions. The development of the different LPO types has been attributed to dislocation slip systems in olivine having different sensitivities to water fugacity, but this hypothesis has not been directly tested. To measure the influence of water fugacity on the relative strengths of olivine dislocation slip systems, we carried out a series of deformation experiments on olivine single crystals under either anhydrous or hydrous conditions. The crystals were oriented to activate either the (010)[100], (001)[100], or (100)[001] dislocation slip systems using a direct shear geometry, which allows for isolation of single slip systems, in contrast to the multiple systems activated in experiments carried out in compression. Post‐deformation electron backscatter diffraction analyses reveal orientation gradients consistent with deformation occurring via the motion of dislocations on the activated slip systems. Crystals in all of the investigated orientations exhibit hydrolytic weakening, but crystals oriented to activate the (001)[100] slip system exhibit the largest degree of weakening. These results are consistent with a water‐induced change in LPO in olivine‐rich rocks deforming by dislocation creep. The rheological data obtained from the experiments can be used to improve models of LPO evolution in Earth's mantle, which is critical for imaging the structure of Earth's interior and predicting the movement of Earth's tectonic plates.
LINC81507 act as a competing endogenous RNA of miR-199b-5p to facilitate NSCLC proliferation and metastasis via regulating the CAV1/STAT3 pathway
Authors: Peng Wei , He Dan , Shan Bin , Wang Jun , Shi Wenwen , Zhao Wenyuan , Peng Zhenzi , Luo Qingxi , Duan Minghao , Li Bin , Cheng Yuanda , Dong Yeping , Tang Faqing , Zhang Chunfang , Duan Chaojun
Published: July 2019

Lung cancer is the leading cause of cancer-related mortality worldwide. Recently, accumulating data indicate that long noncoding RNAs (LncRNAs) function as novel crucial regulators of diverse biological processes, including proliferation and metastasis, in tumorigenesis. Lnc NONHSAT081507.1 (LINC81507) is associated with lung adenocarcinoma. However, its pathological role in non-small cell lung cancer (NSCLC) remains unknown. In our study we investigated the role of LINC81507 in NSCLC. The expression of LINC81507 was analyzed in 105 paired NSCLC tumor specimens and paired adjacent non-tumorous tissues from NSCLC patients by real-time quantitative PCR (RT-qPCR). Gain- and loss-of-function experiments were conducted to investigate the functions of LINC81507, miR-199b-5p and CAV1. Reduced expression of LINC81507 resulted in cell growth, proliferation, migration and epithelial–mesenchymal transition (EMT) in NSCLC cells, whereas ectopic overexpression of LINC81507 resulted in the opposite effects both in vitro and in vivo. Nuclear and Cytoplasmic fractionation assays showed LINC81507 mainly resided in cytoplasm. Bioinformatics analysis and dual-luciferase assays revealed that miR-199b-5p was a direct target of LINC81507 through binding Ago2. Mechanistic analysis demonstrated that miR-199b-5p specifically targeted the Caveolin1 (CAV1) gene, and LINC81507 inactivated the STAT3 pathway in a CAV1-dependent manner. Taken together, LINC81507 is decreased in NSCLC and functions as a sponge to miR-199b-5p to regulate CAV1/STAT3 pathway, which suggests that LINC81507 serve as a tumor suppressor and potential therapeutic target and biomarker for metastasis and prognosis in NSCLC.
C1q/tumor necrosis factor-related protein-3-engineered mesenchymal stromal cells attenuate cardiac impairment in mice with myocardial infarction
Authors: Zhang Zhengbin , Zhu Liwen , Feng Pan , Tan Yanzhen , Zhang Bing , Gao Erhe , Wang Xiaowu , Fan Chongxi , Wang Xiaoming , Yi Wei , Sun Yang
Published: July 2019

Mesenchymal stromal cells (MSCs) transplantation offers an attractive alternative in myocardial infarctive therapy. However, poor cell engraftment and survival limit their restorative capacity. C1q/tumor necrosis factor-related protein-3 (CTRP3) inhibits reverse remodeling after myocardial infarction (MI) and was found to be secreted by MSCs in our preliminary experiments. We examined whether the overexpression of CTRP3 improved the survival of transplanted MSCs and augmented their efficacy on MI and whether silencing CTRP3 attenuated these effects. For gain-of-function analysis, MSCs overexpressing CTRP3 (LvC3-MSCs), control virus-transfected MSCs (LvNull-MSCs), MSCs alone, or phosphate-buffered saline (PBS) were injected into the peripheral areas of the infarction immediately after coronary artery ligation. For loss-of-function analysis, mice subjected to MI were randomized into groups and administered CTRP3-knockdown MSCs (LvshC3-MSCs), Lvshctrl-MSCs, MSCs, or PBS. Survival rates, cardiac function, and myocardial remodeling in mice were evaluated after 4 weeks. Injection of MSCs or LvNull-MSCs improved the left ventricular ejection fraction, inhibited cardiac fibrosis, and regulated cellular profiles of the infarction border zone 4 weeks after MI compared with those in the PBS group. Furthermore, overexpression of hCTRP3 promoted the efficacy of MSCs in the treatment of MI. However, knocking down CTRP3 impaired that. Coculture experiments confirmed that hCTRP3-enriched conditioned medium (CM) promoted MSCs migration and protected against H2O2-induced cell damage. Conversely, CM from C3−/− MSCs (CTRP3 knock out) significantly reduced the migration and antioxidative effects of MSCs. CTRP3 protein alone promoted MSCs proliferation and migration by upregulating matrix metalloproteinase 9 (MMP9) and protecting against oxidation by increasing superoxide dismutase 2 (SOD2) and metallothionein 1/2 (MT1/2) expression; and these effects were blocked by pretreatment with the extracellular signal-regulated kinase (ERK1/2) inhibitor U0126. Overexpression of CTRP3 significantly improved the MSCs-based efficacy on MI by increasing cell survival and retention via a mechanism involving ERK1/2-MMP9 and ERK1/2-SOD2/MT1/2 signaling.
A novel mitochondrial micropeptide MPM enhances mitochondrial respiratory activity and promotes myogenic differentiation
Authors: Lin Yi-Fang , Xiao Man-Huan , Chen Hua-Xing , Meng Yu , Zhao Na , Yang Liang , Tang Haite , Wang Jia-Lei , Liu Xingguo , Zhu Ying , Zhuang Shi-Mei
Published: July 2019

Micropeptides belong to a class of newly identified small molecules with <100 amino acids in length, and their functions remain largely unknown. Here, we identified a novel muscle-enriched micropeptide that was localized to mitochondria (named MPM, micropeptide in mitochondria) and upregulated during in vitro differentiation of C2C12 myoblasts and in vivo early postnatal skeletal muscle development, and muscle regeneration after cardiotoxin (CTX) damage. Downregulation of MPM was observed in the muscular tissues of tibial muscular dystrophy and Duchenne muscular dystrophy patients. Furthermore, MPM silencing inhibited the differentiation of C2C12 myoblasts into myotubes, whereas MPM overexpression stimulated it. MPM−/− mice exhibited smaller skeletal muscle fibers and worse muscle performance, such as decrease in the maximum grip force of limbs, the latency to fall off rotarod, and the exhausting swimming time. Muscle regeneration was also impaired in MPM−/− mice, as evidenced by lower expression of Pax7, MyoD, and MyoG after CTX injection and smaller regenerated myofibers, compared with wild-type mice. Mechanistical investigations based on both gain- and loss-of function studies revealed that MPM increased oxygen consumption and ATP production of mitochondria. Moreover, ectopic expression of PGC-1α, which can enhance mitochondrial respiration, attenuated the inhibitory effect of siMPM on myogenic differentiation. These results imply that MPM may promote myogenic differentiation and muscle fiber growth by enhancing mitochondrial respiratory activity, which highlights the importance of micropeptides in the elaborate regulatory network of both myogenesis and mitochondrial activity and implicates MPM as a potential target for muscular dystrophy therapy.
Combined treatment with emodin and a telomerase inhibitor induces significant telomere damage/dysfunction and cell death
Authors: Liu Rui , Liu Jing , Wang Shuqing , Wang Yinsong , Zhang Tao , liu Yang , Geng Xin , Wang Feng
Published: July 2019

G-quadruplex telomeric secondary structures represent natural replication fork barriers and must be resolved to permit efficient replication. Stabilization of telomeric G4 leads to telomere dysfunctions demonstrated by telomere shortening or damage, resulting in genome instability and apoptosis. Chemical compounds targeting G4 structures have been reported to induce telomere disturbance and tumor suppression. Here, virtual screening was performed in a natural compound library using PyRx to identify novel G4 ligands. Emodin was identified as one of the best candidates, showing a great G4-binding potential. Subsequently, we confirmed that emodin could stabilize G4 structures in vitro and trigger telomere dysfunctions including fragile telomeres, telomere loss, and telomeric DNA damage. However, this telomere disturbance could be rescued by subsequent elevation of telomerase activity; in contrast, when we treated the cells with the telomerase inhibitor BIBR1532 upon emodin treatment, permanent telomere disturbance and obvious growth inhibition of 4T1-cell xenograft tumors were observed in mice. Taken together, our results show for the first time that emodin-induced telomeric DNA damage can upregulate telomerase activity, which may weaken its anticancer effect. The combined use of emodin and the telomerase inhibitor synergistically induced telomere dysfunction and inhibited tumor generation.
A novel mutation in gelatinous drop-like corneal dystrophy and functional analysis
Authors: Nagahara Yukiko , Tsujikawa Motokazu , Takigawa Toru , Xu Peng , Kai Chifune , Kawasaki Satoshi , Nakatsukasa Mina , Inatomi Tsutomu , Kinoshita Shigeru , Nishida Kohji
Published: July 2019

We identified a novel mutation of the tumor-associated calcium signal transducer 2 (TACSTD2) gene in a Japanese patient with gelatinous drop-like corneal dystrophy (GDLD). Genetic analysis revealed a novel homozygous mutation (c.798delG, which may result in frameshift mutation p.Lys267SerfsTer4) in the TACSTD2 gene. This mutated gene was devoid of its original function in helping the claudin (CLDN) 1 and 7 proteins transfer from the cytoplasm to the plasma membrane.
NHC-catalyzed atropoenantioselective synthesis of axially chiral biaryl amino alcohols via a cooperative strategy
Authors: Yang Gongming , Guo Donghui , Meng Di , Wang Jian
Published: July 2019

Axially chiral biaryl amino-alcohols play a pivotal role in organic synthesis and drug discovery. However, only a very few enantioselective methods have been reported to synthesize chiral biaryl amino-alcohols. Therefore, the rapid enantioselective construction of optically active biaryl amino-alcohols still remains a formidable challenge. Here we report an N-heterocyclic carbene (NHC)-catalyzed atropoenantioselective acylation of biphenols triggered by a cooperative strategy consisting of desymmetrization followed by kinetic resolution. This protocol features broad substrate scope and good functional group tolerance, and allows for a rapid construction of axially chiral biaryl amino-alcohols in good to high yields and with excellent enantioselectivities. Furthermore, the structurally diverse axially chiral biaryl amino-alcohol derivatives provide multiple possibilities for chemists to develop catalysts or ligands for different chemical transformations.
Retention of paternal DNA methylome in the developing zebrafish germline
Authors: Skvortsova Ksenia , Tarbashevich Katsiaryna , Stehling Martin , Lister Ryan , Irimia Manuel , Raz Erez , Bogdanovic Ozren
Published: July 2019

Two waves of DNA methylation reprogramming occur during mammalian embryogenesis; during preimplantation development and during primordial germ cell (PGC) formation. However, it is currently unclear how evolutionarily conserved these processes are. Here we characterise the DNA methylomes of zebrafish PGCs at four developmental stages and identify retention of paternal epigenetic memory, in stark contrast to the findings in mammals. Gene expression profiling of zebrafish PGCs at the same developmental stages revealed that the embryonic germline is defined by a small number of markers that display strong developmental stage-specificity and that are independent of DNA methylation-mediated regulation. We identified promoters that are specifically targeted by DNA methylation in somatic and germline tissues during vertebrate embryogenesis and that are frequently misregulated in human cancers. Together, these detailed methylome and transcriptome maps of the zebrafish germline provide insight into vertebrate DNA methylation reprogramming and enhance our understanding of the relationships between germline fate acquisition and oncogenesis.
Zinc-binding to the cytoplasmic PAS domain regulates the essential WalK histidine kinase of Staphylococcus aureus
Authors: Monk Ian R. , Shaikh Nausad , Begg Stephanie L. , Gajdiss Mike , Sharkey Liam K. R. , Lee Jean Y. H. , Pidot Sacha J. , Seemann Torsten , Kuiper Michael , Winnen Brit , Hvorup Rikki , Collins Brett M. , Bierbaum Gabriele , Udagedara Saumya R. , Morey Jacqueline R. , Pulyani Neha , Howden Benjamin P. , Maher Megan J. , McDevitt Christopher A. , King Glenn F. , Stinear Timothy P.
Published: July 2019

WalKR (YycFG) is the only essential two-component regulator in the human pathogen Staphylococcus aureus. WalKR regulates peptidoglycan synthesis, but this function alone does not explain its essentiality. Here, to further understand WalKR function, we investigate a suppressor mutant that arose when WalKR activity was impaired; a histidine to tyrosine substitution (H271Y) in the cytoplasmic Per-Arnt-Sim (PASCYT) domain of the histidine kinase WalK. Introducing the WalKH271Y mutation into wild-type S. aureus activates the WalKR regulon. Structural analyses of the WalK PASCYT domain reveal a metal-binding site, in which a zinc ion (Zn2+) is tetrahedrally-coordinated by four amino acids including H271. The WalKH271Y mutation abrogates metal binding, increasing WalK kinase activity and WalR phosphorylation. Thus, Zn2+-binding negatively regulates WalKR. Promoter-reporter experiments using S. aureus confirm Zn2+ sensing by this system. Identification of a metal ligand recognized by the WalKR system broadens our understanding of this critical S. aureus regulon.
Structural basis for transcription antitermination at bacterial intrinsic terminator
Authors: You Linlin , Shi Jing , Shen Liqiang , Li Lingting , Fang Chengli , Yu Chengzhi , Cheng Wenbo , Feng Yu , Zhang Yu
Published: July 2019

Bacteriophages typically hijack the host bacterial transcriptional machinery to regulate their own gene expression and that of the host bacteria. The structural basis for bacteriophage protein-mediated transcription regulation—in particular transcription antitermination—is largely unknown. Here we report the 3.4 Å and 4.0 Å cryo-EM structures of two bacterial transcription elongation complexes (P7-NusA-TEC and P7-TEC) comprising the bacteriophage protein P7, a master host-transcription regulator encoded by bacteriophage Xp10 of the rice pathogen Xanthomonas oryzae pv. Oryzae (Xoo) and discuss the mechanisms by which P7 modulates the host bacterial RNAP. The structures together with biochemical evidence demonstrate that P7 prevents transcription termination by plugging up the RNAP RNA-exit channel and impeding RNA-hairpin formation at the intrinsic terminator. Moreover, P7 inhibits transcription initiation by restraining RNAP-clamp motions. Our study reveals the structural basis for transcription antitermination by phage proteins and provides insights into bacterial transcription regulation.
Molecular bilayer graphene
Authors: Zhao Xin-Jing , Hou Hao , Fan Xue-Ting , Wang Yu , Liu Yu-Min , Tang Chun , Liu Shun-He , Ding Peng-Peng , Cheng Jun , Lin Dong-Hai , Wang Cheng , Yang Ye , Tan Yuan-Zhi
Published: July 2019

Bilayer graphene consists of two stacked graphene layers bound together by van der Waals interaction. As the molecular analog of bilayer graphene, molecular bilayer graphene (MBLG) can offer useful insights into the structural and functional properties of bilayer graphene. However, synthesis of MBLG, which requires discrete assembly of two graphene fragments, has proved to be challenging. Here, we show the synthesis and characterization of two structurally well-defined MBLGs, both consisting of two π−π stacked nanographene sheets. We find they have excellent stability against variation of concentration, temperature and solvents. The MBLGs show sharp absorption and emission peaks, and further time-resolved spectroscopic studies reveal drastically different lifetimes for the bright and dark Davydov states in these MBLGs.
Building egg-tray-shaped graphenes that have superior mechanical strength and band gap
Authors: Liu Wei , Zhao Lei , Zurek Eva , Xia Jing , Zheng Yong-hao , Lin Hai-qing , Liu Jing-yao , Miao Mao-sheng
Published: July 2019

The major hindrances of implementing graphene in two-dimensional (2D) electronics are both mechanical (the tendency to crumble and form ripples) and electrical (the lack of a band gap). Moreover, the inevitable structural defects in graphene have a profound influence on its physical and chemical properties. Here, we propose a family of 2D egg-tray graphenes constructed by arranging pentagon and heptagon defects in the graphene lattice based on a careful analysis of the topological distribution of minima, maxima, and saddle points. First-principles calculations show that the egg-tray graphenes are dynamically stable, and their energies, which depend on the concentration of pentagons and heptagons, are the lowest among carbon allotropes. These 2D carbon allotropes exhibit a large variation in their electronic properties, ranging from semimetallic to semiconducting, including some allotropes that have Dirac cones in their band structures. Furthermore, some egg-tray graphenes are predicted to have negative Poisson’s ratios. The adsorption of Li atoms on the egg-tray graphenes is considerably stronger than the adsorption on perfect graphene, therefore they may absorb Li more effectively than graphene, which is important for improving the performance of rechargeable Li batteries.
Real-life prescribing of asthmatic treatments in UK general practice over time using 2014 BTS/SIGN steps
Authors: Gayle Alicia , Tebboth Abigail , Pang Marie , Guelfucci Florent , Argoubi Ramzi , Sherman Steven , Mak Vincent
Published: July 2019

The 2014 British Thoracic Society (BTS) and Scottish Intercollegiate Guideline Network (SIGN) guidelines recommend a stepwise approach to asthma management. We investigated the management of asthma in primary care in the UK to understand how real-world practice compares with BTS/SIGN guidelines. Asthma patients were identified from the UK Clinical Practice Research Datalink from September 2006 to August 2016. Aims were to classify patients according to BTS/SIGN steps, describe the proportion of patients transitioning between steps and describe patient demographics and clinical characteristics per group. Overall, 647,308 patients with asthma were identified (40,096 aged 5–11 years; 607,212 aged 12–80 years). Most treated patients were in step 1 or 2 (88.3% of children/67.5% of adults in December 2007; 83.0% of children/67.0% of adults in June 2016). Most patients remained within their treatment step within a 6-month interval (>78% of children and adults throughout the study duration). The proportion of patients stepping up and down reduced from the beginning of the study, although stepping down to step 1 was relatively common in both adults and children. Few patients had a recorded asthma review in the year before reference date (18.8% of children and 14.8% of adults). Although prescribing patterns meant that most patients remained within their treatment step throughout the study, we cannot be sure that this was because their disease was truly stable. The small proportion of patients stepping up/down and the lack of recorded asthma review suggest that patients may not be treated in accordance with BTS/SIGN guidelines.
Publisher Correction: Bone histology provides insights into the life history mechanisms underlying dwarfing in hipparionins
Authors: Orlandi-Oliveras Guillem , Nacarino-Meneses Carmen , Koufos George D. , Köhler Meike
Published: July 2019

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
XPNPEP2 is associated with lymph node metastasis in prostate cancer patients
Authors: Li Fei , Dai Yun , Xu Hao , Huang Kecheng , Zhou Ying , Luo Danfeng , Ma Ding , Xi Ling , Lv Mengqin , Ma Xiangyi
Published: July 2019

As we reported in our previous studies, TMTP1, a tumor-homing peptide, selectively targets highly metastatic tumors and their metastatic foci. Aminopeptidase P2 (XPNPEP2) is a receptor for TMTP1 tumor-homing peptide. However, the biological and clinical significance of Aminopeptidase P2 in human cancers remains unknown. In this study, the high-density multiple organ tumor tissue array was employed for the analysis of XPNPEP2 expression profiles in human specimens. The results showed that XPNPEP2 was moderately expressed in the normal prostate tissues, but significantly decreased in the prostate cancer. Hence we used TCGA, IHC, and ELISA to further analyze the expression of XPNPEP2 in tissues and serum of prostate cancer patients. In general, XPNPEP2 expression was lower in prostate cancer tissue than in normal prostate tissue, but was higher in prostate cancer tissues with local invasion and LN metastasis than in tissues with localized Pca. Western blot clarified XPNPEP2 had a secreted form in the serum. Then the serums of 128 Pca patients, 70 healthy males and 40 prostate hyperplasia patients were obtained for detecting serum XPNPEP2 levels.The results indicated that the concentration of XPNPEP2 in serums of Pca patients with LN metastasis (142.7 ± 14.40 ng/mL) were significantly higher than levels in Pca patients without LN metastasis (61.63 ± 5.50 ng/mL) (p < 0.01). An ROC analysis revealed that the combination of PSA and XPNPEP2 was more efficient than PSA or XPNPEP2 alone for predicting LN metastasis, especially for Pca patients with low serum PSA levels. In summary, serum XPNPEP2 levels when combined with PSA levels may result in increased sensitivity for predicting LN metastasis in Pca patients, especially for patients with low serum PSA levels.
The effects of magnetic treatment on nitrogen absorption and distribution in seedlings of Populus × euramericana ‘Neva’ under NaCl stress
Authors: Liu Xiumei , Zhu Hong , Wang Lu , Bi Sisheng , Zhang Zhihao , Meng Shiyuan , Zhang Ying , Wang Huatian , Song Chengdong , Ma Fengyun
Published: July 2019

A potted experiment with Populus × euramericana ‘Neva’ was carried out to assess whether there are positive effects of magnetic treatment of saline water (MTSW) on nitrogen metabolism under controlled conditions in a greenhouse. Growth properties, nitrogen contents, enzyme activities and metabolite concentrations were determined based on field experiments and laboratory analysis after a 30-day treatment. The results were as follows: (1) Biomass accumulation, root morphological properties and total nitrogen content were improved by MTSW. (2) Magnetization led to a greater increase in nitrate-nitrogen (NO3−-N) content in roots than in leaves, accompanied by greater NO3− efflux and activated nitrate reductase. (3) MTSW led to a higher ammonium-nitrogen (NH4+-N) content and greater uptake of net NH4+ in the leaves than that in the roots. (4) Magnetization stimulated glutamine synthase, glutamate dehydrogenase and glutamate synthase activities, whereas the concentrations of glutathione and oxidized glutathione were increased in leaves but decreased in roots, and the total glutathione content was increased. Overall, these results indicated some beneficial impacts of MTSW on nitrogen translocation under field conditions, especially for equilibrating the distribution of NO3−-N and NH4+-N. Moreover, these findings confirmed the potential of using low-quality water for agriculture.
Probing the role of perception in fear generalization
Authors: Zaman J. , Struyf D. , Ceulemans E. , Beckers T. , Vervliet B.
Published: July 2019

Behavior in novel situations is guided by similarities to previous experiences, a phenomenon known as generalization. Despite the widespread influence of generalization on healthy and pathological behavior, insight into the underlying mechanisms is lacking. It remains unclear whether a failure to notice situational changes contributes to the generalization of learned behavior. We combined a fear conditioning and generalization procedure with a perceptual decision task in humans and found that a failure to perceive a novel stimulus as different from the initial fear-evoking stimulus was associated with increased conditioned responding. These findings demonstrate the potential of a perception-centered approach to better understand (pathological) behavior and its underlying mechanism and are a promising avenue for the development of refined generalization protocols.
PadR-type repressors controlling production of a non-canonical FtsW/RodA homologue and other trans-membrane proteins
Authors: Hauf Samuel , Möller Lars , Fuchs Stephan , Halbedel Sven
Published: July 2019

The Gram-positive bacterium Listeria monocytogenes occurs ubiquitously in the environment and infects humans upon ingestion. It encodes four PadR-like repressors, out of which LftR has been characterized previously and was shown to control gene expression in response to the antibiotic aurantimycin produced by other environmental bacteria. To better understand the PadR regulons of L. monocytogenes, we performed RNA-sequencing with mutants of the other three repressors LadR, LstR and Lmo0599. We show that LadR is primarily responsible for the regulation of the mdrL gene, encoding an efflux pump, while LstR and Lmo0599 mainly regulate their own operons. The lstR operon contains the lmo0421 gene, encoding a homolog of the RodA/FtsW protein family. However, this protein does not possess such functionality, as we demonstrate here. The lmo0599 operon contains two additional genes coding for the hypothetical trans-membrane proteins lmo0600 and lmo0601. A striking phenotype of the lmo0599 mutant is its impaired growth at refrigeration temperature. In light of these and other results we suggest that Lmo0599 should be renamed and propose LltR (listerial low temperature regulator) as its new designation. Based on the nature of the PadR target genes we assume that these repressors collectively respond to compounds acting on the cellular envelope.
Metabolomics Analysis of Skeletal Muscles from FKRP-Deficient Mice Indicates Improvement After Gene Replacement Therapy
Authors: Vannoy Charles Harvey , Leroy Victoria , Broniowska Katarzyna , Lu Qi Long
Published: July 2019

Muscular dystrophy-dystroglycanopathies comprise a heterogeneous and complex group of disorders caused by loss-of-function mutations in a multitude of genes that disrupt the glycobiology of α-dystroglycan, thereby affecting its ability to function as a receptor for extracellular matrix proteins. Of the various genes involved, FKRP codes for a protein that plays a critical role in the maturation of a novel glycan found only on α-dystroglycan. Yet despite knowing the genetic cause of FKRP-related dystroglycanopathies, the molecular pathogenesis of disease and metabolic response to therapeutic intervention has not been fully elucidated. To address these challenges, we utilized mass spectrometry-based metabolomics to generate comprehensive metabolite profiles of skeletal muscle across diseased, treated, and normal states. Notably, FKRP-deficient mice elicit diverse metabolic abnormalities in biomarkers of extracellular matrix remodeling and/or aging, pentoses/pentitols, glycolytic intermediates, and lipid metabolism. More importantly, the restoration of FKRP protein activity following AAV-mediated gene therapy induced a substantial correction of these metabolic impairments. While interconnections of the affected molecular mechanisms remain unclear, our datasets support the notion that global metabolic profiling can be valuable for determining the involvement of previously unsuspected regulatory or pathological pathways as well as identifying potential targets for drug discovery and diagnostics.
Fibrogenesis in Chronic DSS Colitis is Not Influenced by Neutralisation of Regulatory T Cells, of Major T Helper Cytokines or Absence of IL-13
Authors: Creyns Brecht , Cremer Jonathan , Hoshino Tomoaki , Geboes Karel , de Hertogh Gert , Ferrante Marc , Vermeire Séverine , Ceuppens Jan L. , Van Assche Gert , Breynaert Christine
Published: July 2019

Mechanisms underlying fibrogenesis in chronic colitis are largely unknown. There is an urgent need for clinical markers and identification of targets to prevent, treat and limit intestinal fibrosis. This study investigated the contribution of major T cell cytokines and T regulatory cells (Tregs) to inflammation and fibrosis induced in a model of experimental colitis by oral intake of dextran sodium sulphate (DSS) in wild type and IL-13 knock-out C57Bl/6 mice. Inflammation and fibrosis were scored by macroscopic and histological examination and fibrosis was quantified by hydroxyproline. Numbers of Tregs and IFN-γ+, IL-13+ and IL-17A+ CD4+ T helper (Th) cells in mesenteric lymph nodes increased during chronic DSS administration and mRNA for IFN-γ and IL-17 in the inflamed colon tissue was upregulated. However, antibody-mediated neutralisation of IFN-γ or IL-17A/F in a therapeutic setting had no effect on chronic intestinal inflammation and fibrosis. Antibody-mediated depletion of Tregs did not enhance fibrosis, nor did IL-13 deficiency have an effect on the fibrotic disease. These data argue against an important contribution of Tregs and of the cytokines IFN-γ, IL-13, IL-17A, IL-17F in the induction and/or control of fibrosis in this Crohn’s disease like murine model.
Characterization of two putative Dichelobacter nodosus footrot vaccine antigens identifies the first lysozyme inhibitor in the genus
Authors: Humbert Maria Victoria , Jackson Alexandra , Orr Christian M. , Tews Ivo , Christodoulides Myron
Published: July 2019

The Gram-negative anaerobic bacterium Dichelobacter nodosus (Dn) causes footrot in ruminants, a debilitating and highly contagious disease that results in necrotic hooves and significant economic losses in agriculture. Vaccination with crude whole-cell vaccine mixed with multiple recombinant fimbrial proteins can provide protection during species-specific outbreaks, but subunit vaccines containing broadly cross-protective antigens are desirable. We have investigated two D. nodosus candidate vaccine antigens. Macrophage Infectivity Potentiator Dn-MIP (DNO_0012, DNO_RS00050) and Adhesin Complex Protein Dn-ACP (DNO_0725, DNO_RS06795) are highly conserved amongst ~170 D. nodosus isolates in the https://pubmlst.org/dnodosus/ database. We describe the presence of two homologous ACP domains in Dn-ACP with potent C-type lysozyme inhibitor function, and homology of Dn-MIP to other putative cell-surface and membrane-anchored MIP virulence factors. Immunization of mice with recombinant proteins with a variety of adjuvants induced antibodies that recognised both proteins in D. nodosus. Notably, immunization with fimbrial-whole-cell Footvax vaccine induced anti-Dn-ACP and anti-Dn-MIP antibodies. Although all adjuvants induced high titre antibody responses, only antisera to rDn-ACP-QuilA and rDn-ACP-Al(OH)3 significantly prevented rDn-ACP protein from inhibiting lysozyme activity in vitro. Therefore, a vaccine incorporating rDn-ACP in particular could contribute to protection by enabling normal innate immune lysozyme function to aid bacterial clearance.
Genomic analysis of respiratory syncytial virus infections in households and utility in inferring who infects the infant
Authors: Agoti Charles N. , Phan My V. T. , Munywoki Patrick K. , Githinji George , Medley Graham F. , Cane Patricia A. , Kellam Paul , Cotten Matthew , Nokes D. James
Published: July 2019

Infants (under 1-year-old) are at most risk of life threatening respiratory syncytial virus (RSV) disease. RSV epidemiological data alone has been insufficient in defining who acquires infection from whom (WAIFW) within households. We investigated RSV genomic variation within and between infected individuals and assessed its potential utility in tracking transmission in households. Over an entire single RSV season in coastal Kenya, nasal swabs were collected from members of 20 households every 3–4 days regardless of symptom status and screened for RSV nucleic acid. Next generation sequencing was used to generate >90% RSV full-length genomes for 51.1% of positive samples (191/374). Single nucleotide polymorphisms (SNPs) observed during household infection outbreaks ranged from 0–21 (median: 3) while SNPs observed during single-host infection episodes ranged from 0–17 (median: 1). Using the viral genomic data alone there was insufficient resolution to fully reconstruct within-household transmission chains. For households with clear index cases, the most likely source of infant infection was via a toddler (aged 1 to <3 years-old) or school-aged (aged 6 to <12 years-old) co-occupant. However, for best resolution of WAIFW within households, we suggest an integrated analysis of RSV genomic and epidemiological data.
Caffeine intake modulates the functioning of the attentional networks depending on consumption habits and acute exercise demands
Authors: Huertas Florentino , Blasco Esther , Moratal Consuelo , Lupiañez Juan
Published: July 2019

Consume of stimulants (as caffeine) is very usual in different contexts where the performers have to take quick and accurate decisions during physical effort. Decision-making processes are mediated by the attentional networks. An experiment was carried out to examine the effect of caffeine intake on attention (alerting, orienting, and executive control) as a function of consumption habit under two physical exertion conditions (rest vs. aerobic exercise). Two groups of participants with different caffeine consumption profiles (moderate consumers vs. low consumers) performed the Attention Network Test–Interactions under four different conditions regarding activity (rest vs. exercise) and intake (caffeine vs. placebo). Results showed that whereas exercise led to faster reaction times (RT) in all cases, caffeine intake accelerated RT but only at rest and in moderate caffeine consumers. More importantly, caffeine intake reduced the alertness effect in moderate consumers only at the rest condition. No interactions between Intake and Activity were observed in the other attentional networks, with exercise reducing orienting independently of caffeine intake, which suggests that physical exercise and caffeine are different modulators of attention but can interact. Caffeine intake had differential effects on reaction speed at rest and during physical exercise depending on the individual consumption habit. On the basis of these finding it seems that mainly alertness is modulated differently by internal and external “arousing” conditions.
HCV Phylogeography of the General Population and High-Risk Groups in Cyprus Identifies the Island as a Global Sink for and Source of Infection
Authors: Paraskevis Dimitrios , Stylianou Dora C. , Hezka Johana , Stern Zachariah , Oikonomopoulou Martha , Mamais Ioannis ,   Cyprus PWID Network, Georgiou Chrysanthos , Savvopoulou Natasa , Veresies Kyriakos L. , Pavlou Tina , Argyriou Argyris , Zarouna Elena , Kostrikis Leondios G.
Published: July 2019

Hepatitis C virus (HCV) genotype and subtype distribution differs according to geographic origin and transmission risk category. Previous molecular epidemiology studies suggest the presence of multiple subtypes among Cypriot subjects. To investigate HCV genotype- and subtype-specific dissemination patterns, origins, and transmission in Cyprus, we analyzed HCV sequences encoding partial Core-E1 and NS5B regions. Analyzed populations comprised the general population and high-risk cohorts in Cyprus and a globally sampled dataset. Maximum-likelihood phylogeny reconstruction with bootstrap evaluation, character reconstruction using parsimony, and bootstrap trees estimated by ML were performed to identify the geographic origin of HCV subtypes and statistically significant dispersal pathways among geographic regions. Phylogeographic analyses traced the origin of subtypes in the general population and among PWID in Cyprus to unique and overlapping globally distributed regions. Phylogenetic analysis in Core-E1 revealed that most sequences from incarcerated populations in Cyprus clustered with the general population and PWID. We estimate that HCV infections in Cyprus originate from multiple global sources while most HCV transmissions among incarcerated individuals occur locally. This analysis is one of a few studies tracing HCV dispersal patterns using global datasets, and these practices and findings should inform how HCV epidemics are targeted by future prevention policies.
Aerosol mixing state revealed by transmission electron microscopy pertaining to cloud formation and human airway deposition
Authors: Ching Joseph , Adachi Kouji , Zaizen Yuji , Igarashi Yasuhito , Kajino Mizuo
Published: July 2019

Aerosol mixing state is one of the most important factors determining the impacts of aerosol particles on aerosol-cloud-climate interactions and human health. The size, composition, and morphology of about 32,000 single particles are analyzed using transmission electron microscopy (TEM) to evaluate per-particle mixing state. Based on the TEM analysis, we quantify aerosol mixing state and examine the impacts of per-particle mixing state on cloud condensation nuclei (CCN) properties and particle deposition efficiency along the human respiratory tract. Assuming homogeneous chemical composition across the aerosol population, a common practice in many global and regional models to various extents, we show that such simplification of mixing state representation could potentially lead to remarkable errors, a maximum of about 90% and 35%, in CCN concentrations and deposition efficiency calculations respectively. Our results from ambient per-particle observations highlight the importance of considering aerosol mixing state in both air quality models and climate models.