bluuebunny/crossref_metadata_2025 huggingface dataset:
Is There a Classical Inertial Sublayer Over the Amazon Forest?
Authors: Dias‐Júnior Cléo Quaresma , Dias Nelson Luís , dos Santos Rosa Maria N. , Sörgel Matthias , Araújo Alessandro , Tsokankunku Anywhere , Ditas Florian , de Santana Raoni Aquino , von Randow Celso , Sá Marta , Pöhlker Christopher , Toledo Machado Luiz Augusto , de Sá Leonardo Deane , Moran‐Zuloaga Daniel , Janssen Ruud , Acevedo Otávio , Oliveira Pablo , Fisch Gilberto , Chor Tomas , Manzi Antonio
Published: May 2019

On the basis of measurements over different surfaces, an inertial sublayer (ISL), where Monin‐Obukhov Similarity Theory applies, exists above z=3h, where h is canopy height. The roughness sublayer is within h<z<3h. Most studies of the surface layer above forests, however, are able to probe only a narrow region above h. Therefore, direct verification of an ISL above tall forests is difficult. In this study we conducted a systematic analysis of unstable turbulence characteristics at heights from 40 to 325 m, measured at an 80m, and the recently built 325‐m Amazon Tall Tower Observatory towers over the Amazon forest. Our analyses have revealed no indication of the existence of an ISL; instead, the roughness sublayer directly merges with the convective mixed layer above. Implications for estimates of momentum and scalar fluxes in numerical models and observational studies can be significant.
A New Ring Current Model for Saturn
Authors: Carbary J. F.
Published: May 2019

The ring current of Saturn is obtained by taking the curl of the observed magnetic field. An analytical model of this ring current can then be obtained by fitting it to a lognormal in ρ and a Gaussian in z. Local time dependence is included as a harmonic expansion in ϕ for coefficients of the lognormal; radial dependence is included as a quadratic expansion in ρ of the width of the Gaussian. In this model, the ring current peaks at ~0.25 MA/RS2 at ~10 RS on the nightside near ~1 hr. The ring current strength minimizes at ~0.17 MA/RS2 on the dayside near ~16 hr. The cross‐sectional shape of the ring current is a teardrop extending from ~5 to ~20 RS or more.
Whole Atmosphere Climate Change: Dependence on Solar Activity
Authors: Solomon Stanley C. , Liu Han‐Li , Marsh Daniel R. , McInerney Joseph M. , Qian Liying , Vitt Francis M.
Published: May 2019

We conducted global simulations of temperature change due to anthropogenic trace gas emissions, which extended from the surface, through the thermosphere and ionosphere, to the exobase. These simulations were done under solar maximum conditions, in order to compare the effect of the solar cycle on global change to previous work using solar minimum conditions. The Whole Atmosphere Community Climate Model‐eXtended was employed in this study. As in previous work, lower atmosphere warming, due to increasing anthropogenic gases, is accompanied by upper atmosphere cooling, starting in the lower stratosphere, and becoming dramatic, almost 2 K per decade for the global mean annual mean, in the thermosphere. This thermospheric cooling, and consequent reduction in density, is less than the almost 3 K per decade for solar minimum conditions calculated in previous simulations. This dependence of global change on solar activity conditions is due to solar‐driven increases in radiationally active gases other than carbon dioxide, such as nitric oxide. An ancillary result of these and previous simulations is an estimate of the solar cycle effect on temperatures as a function of altitude. These simulations used modest, five‐member, ensembles, and measured sea surface temperatures rather than a fully coupled ocean model, so any solar cycle effects were not statistically significant in the lower troposphere. Temperature change from solar minimum to maximum increased from near zero at the tropopause to about 1 K at the stratopause, to approximately 500 K in the upper thermosphere, commensurate with the empirical evidence, and previous numerical models.
The Mechanism of Methane Gas Migration Through the Gas Hydrate Stability Zone: Insights From Numerical Simulations
Authors: Liu Jinlong , Haeckel Matthias , Rutqvist Jonny , Wang Shuhong , Yan Wen
Published: May 2019

Free gas migration through the gas hydrate stability zone (GHSZ) and subsequent gas seepage at the seabed are characteristic features in marine gas hydrate provinces worldwide. The biogenic or thermogenic gas is typically transported along faults from deeper sediment strata to the GHSZ. Several mechanisms have been proposed to explain free gas transport through the GHSZ. While inhibition of hydrate formation by elevated salinities and temperatures have been addressed previously in studies simulating unfocused, area‐wide upward advection of gas, which is not adequately supported by field observations, the role of focused gas flow through chimney‐like structures has been underappreciated in this context. Our simulations suggest that gas migration through the GHSZ is, fundamentally, a result of methane gas supply in excess of its consumption by hydrate formation. The required high gas flux is driven by local overpressure, built up from gas accumulating below the base of the GHSZ that fractures the overburden when exceeding a critical pressure, thereby creating the chimney‐like migration pathway. Initially rapid hydrate formation raises the temperature in the chimney structure, thereby facilitating further gas transport through the GHSZ. As a consequence, high hydrate saturations form preferentially close to the seafloor, where temperatures drop to bottom water values, producing a prominent subsurface salinity peak. Over time, hydrates form at a lower rate throughout the chimney structure, while initial temperature elevation and salinity peak dissipate. Thus, our simulations suggest that the near‐surface salinity peak and elevated temperatures are a result of transient high‐flux gas migration through the GHSZ.
Effects of Continental Clouds on Surface Aitken and Accumulation Modes
Authors: Noble Stephen R. , Hudson James G.
Published: May 2019

Relationships between clouds and surface aerosol are investigated at the Oklahoma Atmospheric Radiation Measurements Southern Great Plains site. Cloud chemical transformations, coalescence, and Brownian capture increase material within cloud droplets. Then when cloud droplets evaporate, as they often do, their residuals are larger than unnucleated particles. This creates a bimodal particle size distribution by moving some Aitken mode (25‐ to 100‐nm diameter) particles to the accumulation mode (100‐ to 825‐nm diameter). Clouds also block solar radiation that causes photochemical reactions that produce small particles that grow by coagulation and condensation into the Aitken mode. Highly significant positive correlations of remotely sensed cloud fraction (cf) with time‐lagged Aitken and accumulation mode mean particle diameter (mpd) isolated the effects of cloud processing on both modes. Positive correlations of cf with accumulation concentrations and negative correlations of cf with Aitken concentrations also provided evidence of cloud processing. Photochemical production of very small particles under clear daylight skies worked together with cloud processing to enhance Aitken mpd and concentration correlations with cf. Cloud‐processed aerosol was evident only during daylight and when the boundary layer mixing height exceeded the remotely sensed cloud base altitude. Greater cf, especially consecutive high cf hours increased accumulation and Aitken mpd and accumulation concentrations while it decreased Aitken concentrations. Lower cf, especially consecutive hours of no clouds, decreased overall mpd and did not enhance the accumulation mode. All of these results implicated clouds as a source of the accumulation mode, and thus, clouds seemed to explain bimodal aerosol over the mid‐North American continent.
Generation of multiphoton quantum states on silicon
Authors: Zhang Ming , Feng Lan-Tian , Zhou Zhi-Yuan , Chen Yang , Wu Hao , Li Ming , Gao Shi-Ming , Guo Guo-Ping , Guo Guang-Can , Dai Dao-Xin , Ren Xi-Feng
Published: May 2019

Multiphoton quantum states play a critical role in emerging quantum technologies and greatly improve our fundamental understanding of the quantum world. Integrated photonics is well recognized as an attractive technology offering great promise for the generation of photonic quantum states with high-brightness, tunability, stability, and scalability. Herein, we demonstrate the generation of multiphoton quantum states using a single-silicon nanophotonic waveguide. The detected four-photon rate reaches 0.34 Hz even with a low-pump power of 600 μW. This multiphoton quantum state is also qualified with multiphoton quantum interference, as well as quantum state tomography. For the generated four-photon states, the quantum interference visibilities are greater than 95%, and the fidelity is 0.78 ± 0.02. Furthermore, such a multiphoton quantum source is fully compatible with the on-chip processes of quantum manipulation, as well as quantum detection, which is helpful for the realization of large-scale quantum photonic integrated circuits (QPICs) and shows great potential for research in the area of multiphoton quantum science.
nNOS/GSNOR interaction contributes to skeletal muscle differentiation and homeostasis
Authors: Montagna Costanza , Rizza Salvatore , Cirotti Claudia , Maiani Emiliano , Muscaritoli Maurizio , Musarò Antonio , Carrí Maria Teresa , Ferraro Elisabetta , Cecconi Francesco , Filomeni Giuseppe
Published: May 2019

Neuronal nitric oxide synthase (nNOS) plays a crucial role in the maintenance of correct skeletal muscle function due, at least in part, to S-nitrosylation of specific protein targets. Similarly, we recently provided evidence for a muscular phenotype in mice lacking the denitrosylase S-nitrosoglutathione reductase (GSNOR). Here, we demonstrate that nNOS and GSNOR are concomitantly expressed during differentiation of C2C12. They colocalizes at the sarcolemma and co-immunoprecipitate in cells and in myofibers. We also provide evidence that GSNOR expression decreases in mouse models of muscular dystrophies and of muscle atrophy and wasting, i.e., aging and amyotrophic lateral sclerosis, suggesting a more general regulatory role of GSNOR in skeletal muscle homeostasis.
Angiotensin II inhibits apoptosis of mouse aortic smooth muscle cells through regulating the circNRG-1/miR-193b-5p/NRG-1 axis
Authors: Sun Yan , Zhang Suli , Yue Mingming , Li Yang , Bi Jing , Liu Huirong
Published: May 2019

Angiotensin II (Ang II) is known to promote proliferation of vascular smooth muscle cells (VSMCs) in vascular remodeling, but whether it has an anti-apoptotic effect needs to be explored. Neuregulin-1 (NRG-1) as a member of the epidermal growth factor family was reported to suppress the proliferation of VSMCs by activating ErbB receptors, and therefore we hypothesized that there might be a cross talk between the anti-apoptotic effect of Ang II and the anti-proliferative effect of NRG-1 in VSMCs. The aim of the present study was to observe the expression and role of NRG-1 underlying the inhibitory effect of Ang II on apoptosis of mouse aortic smooth muscle cells (MASMCs). It was found that NRG-1 expression was down-regulated via the circNRG-1/miR-193b-5p-mediated post-transcriptional mechanism in response to Ang II. In addition, NRG-1 overexpression reversed the inhibitory effect of Ang II on apoptosis in MASMCs. Our data may provide a molecular basis for further understanding the mechanism of Ang II in suppressing the apoptosis of MASMCs by decreasing NRG-1 expression at circular RNA and micro RNA levels. The circNRG-1/miR-193b-5p/NRG-1 axis may prove to be a potential target for Ang II to inhibit the apoptosis of VSMCs and lead to vascular remodeling.
SIRT1 deacetylated and stabilized XRCC1 to promote chemoresistance in lung cancer
Authors: Yousafzai Neelum Aziz , Zhou Qiyin , Xu Wenxia , Shi Qiqi , Xu Jinye , Feng Lifeng , Chen Hui , Shin Vivian Yvonne , Jin Hongchuan , Wang Xian
Published: May 2019

Chemoresistance is one of the most important challenges in the clinical management of lung cancer. SIRT1 is a NAD dependent protein deacetylase and implicated in diverse cellular processes such as DNA damage repair, and cancer progression. SIRT1 is upregulated in chemoresistant lung cancer cells, genetic knockdown or chemical inhibition of SIRT1 reversed chemoresistance by enhancing DNA damage and apoptosis activation, accompanied with XRCC1 degradation. E3 ligase β-TrCP catalyzed the poly-ubiquitination of XRCC1 to promote its proteasome-dependent degradation. SIRT1 bound and deacetylated XRCC1 at lysine K260, K298 and K431, preventing it from β-TrCP-dependent ubiquitination. Mutations of these three lysine sites in XRCC1 abrogated the interaction with β-TrCP and prolonged the half-life of XRCC1 protein. Here, we describes SIRT1 confers chemoresistance to lung cancer cells by deacetylating and stabilizing XRCC1. Therefore, targeting SIRT1 might be a new strategy to manage the chemoresistance of lung cancer, and probably other cancers.
PRMT1 regulates the tumour-initiating properties of esophageal squamous cell carcinoma through histone H4 arginine methylation coupled with transcriptional activation
Authors: Zhao Yue , Lu Qijue , Li Chunguang , Wang Xinyu , Jiang Long , Huang Lei , Wang Chao , Chen Hezhong
Published: May 2019

Esophageal squamous cell carcinoma (ESCC) is the most difficult subtype of esophageal cancer to treat due to a paucity of effective targeted therapy. ESCC is believed to arise from tumour initiating cells (TICs), which contribute to metastasis and chemoresistance. In this study, we found that Protein arginine methyltransferase 1(PRMT1) was highly expressed in ESCCs and associated with aberrant clinicopathological characteristics of ESCC patients. In ESCC specimens, the elevated expression of PRMT1 and OV6 was significantly associated with histologic grade, TNM stage and poor patient prognosis. Moreover, overexpression of PRMT1 was observed in esophageal TICs purified by magnetic sorting of adherent and spheroid ECA109/TE1 cells. The increased level of PRMT1 in TICs facilitated the expression of TIC markers, stem cell-like properties, resistance to chemotherapy, tumorigenicity and increased their percentages in ECSS samples. Conversely, knockdown of PRMT1 significantly diminished the self-renewal properties of ESCC. Moreover, we show that PRMT1 can catalyse histone H4R3 asymmetric dimethylation and promote transcription activation of down-stream genes. Further RNA-Seq transcriptome analysis reveals that overexpression of PRMT1 in ESCC cell lines activates Wnt/β-catenin and Notch signaling pathway. Together, our studies highlight that PRMT1 activates and maintains esophageal TICs by mediating transcription alteration through histone H4 arginine methylation.
ALK5 signaling pathway mediates neurogenesis and functional recovery after cerebral ischemia/reperfusion in rats via Gadd45b
Authors: Zhang Keming , Zhang Qinbin , Deng Jing , Li Jinfang , Li Jiani , Wen Lan , Ma Jingxi , Li Changqing
Published: May 2019

Transforming growth factor β (TGF-β) serves critical functions in brain injury, especially in cerebral ischemia; however, apart from its neuroprotective effects, its role in regulating neurogenesis is unclear. TGF-β acts in different ways; the most important, canonical TGF-β activity involves TGF-β receptor I (TβRI) or the activin receptor-like kinase 5 (ALK5) signaling pathway. ALK5 signaling is a major determinant of adult neurogenesis. In our previous studies, growth arrest and DNA damage protein 45b (Gadd45b) mediated axonal plasticity after stroke. Here, we hypothesized that ALK5 signaling regulates neural plasticity and neurological function recovery after cerebral ischemia/reperfusion (I/R) via Gadd45b. First, ALK5 expression was significantly increased in middle cerebral artery occlusion/reperfusion (MCAO/R) rats. Then, we knocked down or overexpressed ALK5 with lentivirus (LV) in vivo. ALK5 knockdown reduced axonal and dendritic plasticity, with a concomitant decrease in neurological function recovery. Conversely, ALK5 overexpression significantly increased neurogenesis as well as functional recovery. Furthermore, ALK5 mediated Gadd45b protein levels by regulating Smad2/3 phosphorylation. Finally, ALK5 coimmunoprecipitated with Gadd45b. Our results suggested that the ALK5 signaling pathway plays a critical role in mediating neural plasticity and neurological function recovery via Gadd45b after cerebral ischemia, representing a new potential target for cerebral I/R injury.
AXL degradation in combination with EGFR-TKI can delay and overcome acquired resistance in human non-small cell lung cancer cells
Authors: Kim Donghwa , Bach Duc-Hiep , Fan Yan-Hua , Luu Thi-Thu-Trang , Hong Ji-Young , Park Hyen Joo , Lee Sang Kook
Published: May 2019

Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has been a major obstacle in the treatment of non-small cell lung cancer (NSCLC) patients. AXL has been reported to mediate EGFR-TKIs. Recently, third generation EGFR-TKI osimertinib has been approved and yet its acquired resistance mechanism is not clearly understood. We found that AXL is involved in both gefitinib and osimertinib resistance using in vitro and in vivo model. In addition, AXL overexpression was correlated with extended protein degradation rate. We demonstrate targeting AXL degradation is an alternative route to restore EGFR-TKIs sensitivity. We confirmed that the combination effect of YD, an AXL degrader, and EGFR-TKIs can delay or overcome EGFR-TKIs-driven resistance in EGFR-mutant NSCLC cells, xenograft tumors, and patient-derived xenograft (PDX) models. Therefore, combination of EGFR-TKI and AXL degrader is a potentially effective treatment strategy for overcoming and delaying acquired resistance in NSCLC.
Mechanism-based tuning of insect 3,4-dihydroxyphenylacetaldehyde synthase for synthetic bioproduction of benzylisoquinoline alkaloids
Authors: Vavricka Christopher J. , Yoshida Takanobu , Kuriya Yuki , Takahashi Shunsuke , Ogawa Teppei , Ono Fumie , Agari Kazuko , Kiyota Hiromasa , Li Jianyong , Ishii Jun , Tsuge Kenji , Minami Hiromichi , Araki Michihiro , Hasunuma Tomohisa , Kondo Akihiko
Published: May 2019

Previous studies have utilized monoamine oxidase (MAO) and L-3,4-dihydroxyphenylalanine decarboxylase (DDC) for microbe-based production of tetrahydropapaveroline (THP), a benzylisoquinoline alkaloid (BIA) precursor to opioid analgesics. In the current study, a phylogenetically distinct Bombyx mori 3,4-dihydroxyphenylacetaldehyde synthase (DHPAAS) is identified to bypass MAO and DDC for direct production of 3,4-dihydroxyphenylacetaldehyde (DHPAA) from L-3,4-dihydroxyphenylalanine (L-DOPA). Structure-based enzyme engineering of DHPAAS results in bifunctional switching between aldehyde synthase and decarboxylase activities. Output of dopamine and DHPAA products is fine-tuned by engineered DHPAAS variants with Phe79Tyr, Tyr80Phe and Asn192His catalytic substitutions. Balance of dopamine and DHPAA products enables improved THP biosynthesis via a symmetrical pathway in Escherichia coli. Rationally engineered insect DHPAAS produces (R,S)-THP in a single enzyme system directly from L-DOPA both in vitro and in vivo, at higher yields than that of the wild-type enzyme. However, DHPAAS-mediated downstream BIA production requires further improvement.
Fluidal pyroclasts reveal the intensity of peralkaline rhyolite pumice cone eruptions
Authors: Clarke Ben , Calder Eliza S. , Dessalegn Firawalin , Fontijn Karen , Cortés Joaquín A. , Naylor Mark , Butler Ian , Hutchison William , Yirgu Gezahegn
Published: May 2019

Peralkaline rhyolites are medium to low viscosity, volatile-rich magmas typically associated with rift zones and extensional settings. The dynamics of peralkaline rhyolite eruptions remain elusive with no direct observations recorded, significantly hindering the assessment of hazard and risk. Here we describe uniquely-preserved, fluidal-shaped pyroclasts found within pumice cone deposits at Aluto, a peralkaline rhyolite caldera in the Main Ethiopian Rift. We use a combination of field-observations, geochemistry, X-ray computed microtomography (XCT) and thermal-modelling to investigate how these pyroclasts are formed. We find that they deform during flight and, depending on size, quench prior to deposition or continue to inflate then quench in-situ. These findings reveal important characteristics of the eruptions that gave rise to them: that despite the relatively low viscosity of these magmas, and similarities to basaltic scoria-cone deposits, moderate to intense, unstable, eruption columns are developed; meaning that such eruptions can generate extensive tephra-fall and pyroclastic density currents.
Author Correction: Engineering of high-precision base editors for site-specific single nucleotide replacement
Authors: Tan Junjie , Zhang Fei , Karcher Daniel , Bock Ralph
Published: May 2019

The original version of this Article contained an error in Figure 5. In the panel c, the right bar chart was inadvertently replaced with a duplicate of the left bar chart. This has been corrected in both the PDF and HTML versions of the Article.
Author Correction: Structural and pharmacological basis for the induction of mitochondrial biogenesis by formoterol but not clenbuterol
Authors: Cameron Robert B. , Peterson Yuri K. , Beeson Craig C. , Schnellmann Rick G.
Published: May 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.
Electrocardiogram generation with a bidirectional LSTM-CNN generative adversarial network
Authors: Zhu Fei , Ye Fei , Fu Yuchen , Liu Quan , Shen Bairong
Published: May 2019

Heart disease is a malignant threat to human health. Electrocardiogram (ECG) tests are used to help diagnose heart disease by recording the heart’s activity. However, automated medical-aided diagnosis with computers usually requires a large volume of labeled clinical data without patients' privacy to train the model, which is an empirical problem that still needs to be solved. To address this problem, we propose a generative adversarial network (GAN), which is composed of a bidirectional long short-term memory(LSTM) and convolutional neural network(CNN), referred as BiLSTM-CNN,to generate synthetic ECG data that agree with existing clinical data so that the features of patients with heart disease can be retained. The model includes a generator and a discriminator, where the generator employs the two layers of the BiLSTM networks and the discriminator is based on convolutional neural networks. The 48 ECG records from individuals of the MIT-BIH database were used to train the model. We compared the performance of our model with two other generative models, the recurrent neural network autoencoder(RNN-AE) and the recurrent neural network variational autoencoder (RNN-VAE). The results showed that the loss function of our model converged to zero the fastest. We also evaluated the loss of the discriminator of GANs with different combinations of generator and discriminator. The results indicated that BiLSTM-CNN GAN could generate ECG data with high morphological similarity to real ECG recordings.
Native soil microorganisms hinder the soil enrichment with antibiotic resistance genes following manure applications
Authors: Pérez-Valera Eduardo , Kyselková Martina , Ahmed Engy , Sladecek Frantisek Xaver Jiri , Goberna Marta , Elhottová Dana
Published: May 2019

Bacterial genes responsible for resistance to antibiotic agents (ARG) are spread from livestock to soil through application of manure, threatening environmental and human health. We investigated the mechanisms of ARG dissemination and persistence to disentangle i) the influence of nutrients and microorganisms on the soil tetracycline (TET) resistome, and ii) the role of indigenous soil microbiota in preventing ARG spread. We analysed short-term (7 days) and persistent (84 days) effects of manure on the resistome of three antibiotic-free pasture soils. Four microcosm treatments were evaluated: control, mineral nutrient fertilization, and deposition of a layer of fresh manure onto soil or γ-irradiated soil. We quantified five TET-resistance genes, isolated 135 TET-resistant bacteria and sequenced both culturable TET-resistant and whole bacterial communities. Manure amendments, but not nutrient addition, increased the abundance of TET-r genes such as tet(Y). Such changes persisted with time, in contrast with the TET-resistant bacterial composition, which partially recovered after manure amendments. Manured γ-irradiated soils showed significantly lower nutrient content and higher TET-r gene abundance than non-irradiated soils, suggesting that native soil bacteria are essential for the fertilization effect of manure on soil as well as control the dissemination of potentially risky TET-r genes.
Drug-like Fragments Inhibit agr-Mediated Virulence Expression in Staphylococcus aureus
Authors: Bezar Ian F. , Mashruwala Ameya A. , Boyd Jeffrey M. , Stock Ann M.
Published: May 2019

In response to the increasingly problematic emergence of antibiotic resistance, novel strategies for combating pathogenic bacteria are being investigated. Targeting the agr quorum sensing system, which regulates expression of virulence in Staphylococcus aureus, is one potentially useful approach for combating drug-resistant pathogens that has not yet been fully explored. A previously published study of a fragment screen resulted in the identification of five compound fragments that interact with the DNA-binding domain of the response regulator AgrA from S. aureus. We have analyzed the ability of these compounds to affect agr-mediated virulence gene expression in cultured S. aureus cells. Three of the compounds demonstrated the ability to reduce agr-driven transcription at the P2 and P3 promoters of the agr operon and increase biofilm formation, and two of these compounds also showed the ability to reduce levels of secreted toxins. The finding that the compounds tested were able to reduce agr activity suggests that they could be useful tools for probing the effects of agr inhibition. Furthermore, the characteristics of compound fragments make them good starting materials for the development of compound libraries to iteratively improve the inhibitors.
Downregulation of thromboxane A2 and angiotensin II type 1 receptors associated with aging-related decrease in internal anal sphincter tone
Authors: Mohanty Ipsita , Singh Jagmohan , Rattan Satish
Published: May 2019

Aging-associated decrease in internal anal sphincter (IAS) tone (AADI) is a major contributor in the rectoanal incontinence (RI). To determine the pathogenesis of AADI, we investigated the effect of aging on GPCR activation and related downstream signaling. We particularly investigated two GPCRs that characterize IAS smooth muscle cells (SMCs): thromboxane A2 and angiotensin II type 1. Two groups of Fischer 344 rats (6-month-old [young group] and 26-month-old [old group]) were employed to determine the GPCR function by isometric contraction, the expressions of GPCRs, and their downstream regulatory signaling proteins (regulator of G-protein signaling 2, RGS2; GPCR Kinase 5, GRK5; and β-arrestin, Arrb2) using RT-PCR, qPCR, and western blot analyses. We used reversible biotinylation to monitor the GPCR trafficking using SMCs. Aging selectively attenuated thromboxane A2 and Ang II-induced IAS contraction. RT-PCR, qPCR, and WB data revealed a significant decrease in the expressions of the GPCRs and increase in the expression of RGS2, GRK5, and Arrb2. The increased GPCR internalization and decreased recycling under aging were validated by reversible biotinylation. We conclude that downregulation of GPCR, accompanied by upregulation of regulatory proteins, plays an important role in receptor desensitization and may be important underlying mechanisms of RI in certain aging patients.
Automated generation of Kochen-Specker sets
Authors: Pavičić Mladen , Waegell Mordecai , Megill Norman D. , Aravind P. K.
Published: May 2019

Quantum contextuality turns out to be a necessary resource for universal quantum computation and also has applications in quantum communication. Thus it becomes important to generate contextual sets of arbitrary structure and complexity to enable a variety of implementations. In recent years, such generation has been done for contextual sets known as Kochen-Specker sets. Up to now, two approaches have been used for massive generation of non-isomorphic Kochen-Specker sets: exhaustive generation up to a given size and downward generation from master sets and their associated coordinatizations. Master sets were obtained earlier from serendipitous or intuitive connections with polytopes or Pauli operators, and more recently from arbitrary vector components using an algorithm that generates orthogonal vector groupings from them. However, both upward and downward generation face an inherent exponential complexity barrier. In contrast, in this paper we present methods and algorithms that we apply to downward generation that can overcome the exponential barrier in many cases of interest. These involve tailoring and manipulating Kochen-Specker master sets obtained from a small number of simple vector components, filtered by the features of the sets we aim to obtain. Some of the classes of Kochen-Specker sets we generate contain all previously known ones, and others are completely novel. We provide examples of both kinds in 4- and 6-dim Hilbert spaces. We also give a brief introduction for a wider audience and a novice reader.
Chemovirotherapeutic Treatment Using Camptothecin Enhances Oncolytic Measles Virus-Mediated Killing of Breast Cancer Cells
Authors: Tai Chen-Jei , Liu Ching-Hsuan , Pan Yu-Chi , Wong Shu Hui , Tai Cheng-Jeng , Richardson Christopher D. , Lin Liang-Tzung
Published: May 2019

Oncolytic virotherapy represents an emerging development in anticancer therapy. Although it has been tested against a variety of cancers, including breast cancer, the efficacy of oncolytic viral vectors delivered as a monotherapy is limited. Enhancing viral oncolytic therapies through combination treatment with anticancer agents is a feasible strategy. In this study, we considered a chemovirotherapeutic approach for treating breast adenocarcinoma using oncolytic measles virus (MV) and the chemotherapeutic agent camptothecin (CPT). Our results demonstrated that co-treatment of MV with CPT yielded enhanced cytotoxicity against breast cancer cells. Low dosage CPT combined with MV was also found to elicit the same therapeutic effect as high doses of CPT. At the lower dosage used, CPT did not inhibit the early stages of MV entry, nor reduce viral replication. Further studies revealed that co-treatment induced significantly enhanced apoptosis of the breast cancer cells compared to either MV or CPT alone. Overall, our findings demonstrate the potential value of MV plus CPT as a novel chemovirotherapeutic treatment against breast cancer and as a strategy to enhance MV oncolytic activity.
Variational principle for scale-free network motifs
Authors: Stegehuis Clara , Hofstad Remco van der , van Leeuwaarden Johan S. H.
Published: May 2019

For scale-free networks with degrees following a power law with an exponent τ ∈ (2, 3), the structures of motifs (small subgraphs) are not yet well understood. We introduce a method designed to identify the dominant structure of any given motif as the solution of an optimization problem. The unique optimizer describes the degrees of the vertices that together span the most likely motif, resulting in explicit asymptotic formulas for the motif count and its fluctuations. We then classify all motifs into two categories: motifs with small and large fluctuations.
Optimizing Measurement of Vascular Endothelial Growth Factor in Small Blood Samples of Premature Infants
Authors: Lopez Yomayuza Claudia C. , Preissner Klaus T. , Lorenz Birgit , Stieger Knut
Published: May 2019

To establish a method that allows for the reliable assessment of vascular endothelial growth factor (VEGF-A) concentrations in very small blood samples of preterm infants. Systemic VEGF measurements are important in view of the most appropriate Anti-VEGF drug to be used for the treatment of acute retinopathy of prematurity (ROP). Cord blood samples from preterm (n = 6) infants, blood samples from preterm infants with treatment requiring ROP (n = 12), and blood samples from healthy adults (n = 10) were collected. Serum, citrate plasma, and serum from recalcified citrate blood were obtained. Levels of VEGF-A and platelet factor-4 (PF-4) were quantified by ELISA or AlphaLISA immunoassay. VEGF-A levels could be detected by both assays, with the AlphaLISA generating slightly lower levels in healthy adults, but not in cord blood of preterm infants. In plasma samples, VEGF levels ranged from non detectable to 181 pg/ml. PF-4 concentrations were between 0.16–3.88 µg/ml. Values of VEGF-A and PF-4 in serum and recalcified serum were significantly higher compared to plasma through the release of these cytokines after platelet activation. In plasma samples of infants with ROP, VEGF-A could always be detected and its values ranged from 19.50 to 245.91 pg/ml and PF-4 concentrations were between 0.1 and 3.3 µg/ml. Using the AlphaLISA kit, we were able to detect VEGF in small sample volumes (5 µl plasma or serum/well) in premature infants with treatment requiring ROP and to monitor platelet activation by PF-4 detection. Minimal blood probe volumes reduce phlebotomy losses avoiding the risk of iatrogenic anemia, thus allowing close monitoring of the cytokine levels in these very fragile infants.
Publisher Correction: Lipidome determinants of maximal lifespan in mammals
Authors: Bozek Katarzyna , Khrameeva Ekaterina E. , Reznick Jane , Omerbašić Damir , Bennett Nigel C. , Lewin Gary R. , Azpurua Jorge , Gorbunova Vera , Seluanov Andrei , Regnard Pierrick , Wanert Fanelie , Marchal Julia , Pifferi Fabien , Aujard Fabienne , Liu Zhen , Shi Peng , Pääbo Svante , Schroeder Florian , Willmitzer Lothar , Giavalisco Patrick , Khaitovich Philipp
Published: May 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.
Pyrogen retention: Comparison of the novel medium cut-off (MCO) membrane with other dialyser membranes
Authors: Hulko Michael , Dietrich Verena , Koch Ilona , Gekeler Alexander , Gebert Michael , Beck Werner , Krause Bernd
Published: May 2019

Haemodialysis effectively removes small solutes and smaller-sized middle molecules from the blood; however, the clearance of larger middle molecules, which have been associated with negative effects, is poor. The novel medium cut-off (MCO) dialysis membrane has larger pore sizes and a more open structure than other high-flux membranes, providing improved removal of larger middle molecules while retaining albumin. However, larger pore sizes may potentially increase permeability to pyrogens, including endotoxins and other bacterial contaminants, that could be present in the dialysis fluid. In this study, we tested the capacity of low-flux, high-flux, MCO and high cut-off dialyser membranes with different pore sizes to prevent pyrogens crossing from dialysate to the blood side in a closed-loop test system, differentiating among lipopolysaccharides, peptidoglycans and bacterial DNA using a toll-like receptor assay. Even though the bacterial contamination levels in our test system exceeded the acceptable pyrogen dose for standard dialysis fluid, levels of lipopolysaccharides, peptidoglycans and bacterial DNA in the blood-side samples were too low to identify potential differences in pyrogen permeability among the membranes. Our results suggest that MCO membranes are suitable for haemodialysis using ISO standard dialysis fluid quality, and retain endotoxins at a similar level as other membranes.
Combination of Repurposed Drug Diosmin with Amoxicillin-Clavulanic acid Causes Synergistic Inhibition of Mycobacterial Growth
Authors: Pushkaran Anju Choorakottayil , Vinod Vivek , Vanuopadath Muralidharan , Nair Sudarslal Sadasivan , Nair Shantikumar V. , Vasudevan Anil Kumar , Biswas Raja , Mohan Chethampadi Gopi
Published: May 2019

Effective therapeutic regimens for the treatment of tuberculosis (TB) are limited. They are comprised of multiple drugs that inhibit the essential cellular pathways in Mycobacterium tuberculosis (Mtb). The present study investigates an approach which enables a combination of Amoxicillin-Clavulanic acid (AMC) and a repurposed drug for its synergistic effect towards TB treatment. We identified Diosmin (DIO), by targeting the active site residues of L,D-transpeptidase (Ldt) enzymes involved in Mtb cell wall biosynthesis by using a structure-based drug design method. DIO is rapidly converted into aglycone form Diosmetin (DMT) after oral administration. Binding of DIO or DMT towards Ldt enzymes was studied using molecular docking and bioassay techniques. Combination of DIO (or DMT) and AMC exhibited higher mycobactericidal activity against Mycobacterium marinum as compared to individual drugs. Scanning electron microscopy study of M. marinum treated with AMC-DIO and AMC-DMT showed marked cellular leakage. M. marinum infected Drosophila melanogaster fly model showed an increased fly survival of ~60% upon treatment with a combination of AMC and DIO (or DMT). Finally, the enhanced in vitro antimicrobial activity of AMC-DIO was validated against Mtb H37Ra and a MDR clinical isolate. Our results demonstrate the potential for AMC and DIO (or DMT) as a synergistic combination for the treatment of TB.
Seasonal synchronization of sleep timing in industrial and pre-industrial societies
Authors: Martín-Olalla José María
Published: May 2019

Artificial light has reshaped human sleep/wake cycle in industrial societies and raised concern on the misalignment of this cycle relative to the light and dark cycle. This manuscript contrasts sleep timing in extratropical, industrial societies (data from eight national time use surveys in countries with Daylight Saving Time —DST— regulations) and Subtropical, pre-industrial societies with and without access to artificial light (data from nine locations coming from seven previous reports) against the cycle of light and dark. Within the two process model of sleep, results show sleep onset and sleep offset keep bound to each other by the homeostatic process. In winter, the photoreceptive process aligns the phase of the sleep/wake cycle to sunrise. As a result the phase increasingly lags with increasing latitude up to a delay of 120 min at 55° latitude. In summer, the homeostatic process still binds sleep onset to speep offset but DST rules in industrialized societies reduce the lag by one third to 40 min at 55° latitude. Sleep timing is then stationary with latitude. The phase of the sleep/wake cycle is then governed by natural trends and no clues of misalignment are revealed.
Dense Quantum Measurement Theory
Authors: Gyongyosi Laszlo , Imre Sandor
Published: May 2019

Quantum measurement is a fundamental cornerstone of experimental quantum computations. The main issues in current quantum measurement strategies are the high number of measurement rounds to determine a global optimal measurement output and the low success probability of finding a global optimal measurement output. Each measurement round requires preparing the quantum system and applying quantum operations and measurements with high-precision control in the physical layer. These issues result in extremely high-cost measurements with a low probability of success at the end of the measurement rounds. Here, we define a novel measurement for quantum computations called dense quantum measurement. The dense measurement strategy aims at fixing the main drawbacks of standard quantum measurements by achieving a significant reduction in the number of necessary measurement rounds and by radically improving the success probabilities of finding global optimal outputs. We provide application scenarios for quantum circuits with arbitrary unitary sequences, and prove that dense measurement theory provides an experimentally implementable solution for gate-model quantum computer architectures.
Defensive peripersonal space is modified by a learnt protective posture
Authors: Biggio Monica , Bisio Ambra , Ruggeri Piero , Bove Marco
Published: May 2019

The Hand Blink Reflex (HBR) is a subcortical defensive response, elicited by the electrical stimulation of the median nerve. HBR increases when the stimulated hand is inside the defensive peripersonalspace (DPPS) of the face. However, the presence of a screen protecting the face could reduce the amplitude of this response. This work aimed to investigate whether the learning of a posture intended to protect the head could modulate the HBR responses. Boxing athletes learn a defensive posture consisting of blocking with arms opponent’s blow towards the face. Two groups were recruited: 13 boxers and 13 people naïve to boxing. HBR response was recorded and elicited in three hand positions depending on the distance from the face. A suppression of HBR enhancement in the static position close to the face was observed in boxer group, contrary to the control group. Also, the higher years of practice in boxing, the higher suppression occurred. However, this suppression was not observed when boxers were asked to move the hand up-to/down-from the face. These findings might suggest that the sensorimotor experience related to a previously learnt protective posture can modify the HBR and thus shape the dimension of the DPPS.
Author Correction: Resonant plasma excitation by single-cycle THz pulses
Authors: Curcio A. , Marocchino A. , Dolci V. , Lupi S. , Petrarca M.
Published: May 2019

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
Eggs are a Natural Functional Food
Authors: Fernandez Maria Luz , Lemos Bruno
Published: May 2019

Functional foods are characterized by containing nutraceuticals or compounds that are known to protect against chronic disease. Based on this definition, eggs are a natural functional food because they contain highly bioavailable carotenoids, lutein and zeaxanthin, and they are a good source of choline. Lutein and zeaxanthin are potent antioxidants that have been shown to decrease systemic inflammation, fatty liver disease and atherosclerosis in animal studies. Further, clinical interventions and epidemiological data document the role of lutein and zeaxanthin in protecting against age-related macular degeneration and in decreasing inflammatory markers in plasma. Choline has been reported to protect against hepatic steatosis. Further, choline has a role as a neurotransmitter and has been shown to increase memory and protect against Alzheimer's disease. In addition, eggs are an excellent source of protein, with all the essential amino acids, which has been demonstrated to preserve muscle strength and decrease appetite. In this chapter, the evidence of eggs as a natural functional food is presented, as well as the antioxidant and anti-inflammatory effects of their components, and their role in the prevention of chronic disease.
Egg Consumption for Appetite Control and Body Weight Regulation
Authors: Son Myoungjin , Wang Xiaofeng , Wu Jianping
Published: May 2019

The prevalence of overweight and obesity is increasing worldwide. There is increasing evidence that a high-protein diet may contribute to body weight loss by increasing satiety. Egg protein is of particular interest as a potential food commodity for weight management because it is an inexpensive source of high-quality nutritional protein. The satiety effect of egg protein in humans and its possible regulatory mechanism has been investigated. At present, the role of egg protein in appetite control and body weight reduction remains controversial; however, there is convincing evidence showing that high egg diets increase satiety compared to low egg diets via increasing the secretion of anorexigenic hormones, such as peptide YY (PYY) and glucagon-like peptide-1 (GLP-1). Some evidence also suggests that high egg consumption results in increased weight loss and improved metabolic syndrome indexes, but the results have not been consistent. Future study on the long-term effects with a more precise diet-assessment method and the use of an accurate index of obesity would help to clarify the effects of eggs on appetite control and obesity.
Egg Consumption and Cardiometabolic Health
Authors: Azarcoya-Barrera Jessy , Field Catherine J. , Jacobs Rene L. , Richard Caroline
Published: May 2019

Despite the fact that the Dietary Guidelines for Americans 2015–2020 no longer emphasize limiting dietary cholesterol intake, confusion remains regarding egg consumption, a rich source of dietary cholesterol, which has historically been linked to increased risk of cardiovascular disease (CVD). In addition, eggs are a rich source of phosphatidylcholine, a form of choline and a precursor of TMAO (trimethylamine N-oxide), an emerging risk factor for CVD. The purpose of this book chapter is to review the existing literature regarding egg consumption and its relationship with CVD risk factors in both healthy and individuals at risk of CVD, and to determine whether eggs should be considered as part of a healthy dietary pattern. The available evidence so far suggests that egg consumption (between 1–3 eggs per day) has little effect on most traditional and non-traditional CVD risk factors, including inflammation, endothelial function, and plasma TMAO and low-density lipoprotein-cholesterol (LDL-C) concentrations. However, egg consumption seems to improve LDL particle phenotype by increasing the number of large LDL particles. Moreover, increases in HDL-C concentrations were consistently observed with egg consumption in both healthy individuals and those at risk of CVD. Despite the lack of evidence that relates egg consumption with CVD, the variability of study designs and populations included makes further investigations necessary.
Egg Carotenoids for Eye Health
Authors: Handelman Garry
Published: May 2019

The center of the human retina contains a high concentration of two carotenoids, lutein (L) and zeaxanthin (Z). This region of the retina is called the macula and is important for high visual acuity. The carotenoids in the macula are abundant in the yolk of chicken eggs when the chickens are fed a diet enriched in corn and the lipid matrix of the egg yolk provides enhanced bioavailability. A 1 mg dose of L and Z from eggs is about 4× more readily absorbed from the diet than 1 mg from a plant source, such as spinach. This evidence supports the hypothesis that diets with frequent egg consumption are an excellent dietary source of L + Z. The best-established function of L + Z in the macula is to improve central visual acuity by reduction of chromatic aberration caused by blue-wavelength light reaching the retina. L + Z may contribute to the prevention of age-related macular degeneration by protecting blue-light-sensitive photoreceptors. Diets that contain eggs rich in L + Z consistently increase plasma levels of L + Z and may increase macular pigment levels if provided for a long duration, typically several months. Epidemiological studies support these visual benefits of eggs; controlled intervention trials would provide the most compelling evidence.