bluuebunny/crossref_metadata_2025 huggingface dataset:
Ultra Wideband Radar Cross Section Reduction by Using Polarization Conversion Metasurfaces
Authors: Ameri Edris , Esmaeli Seyed Hassan , Sedighy Seyed Hassan
Published: January 2019

In this paper, a polarization conversion metasurface (PCM) is designed for ultra wideband radar cross section (RCS) reduction. The proposed polarization conversion metasurface consists of double-heads arrow unit cell with its 90°, 180° and 270° rotated ones to create the destructive interferences cancellation and radar cross section (RCS) reduction, consequently. The proposed metasurface demonstrates ultra-wide band 10-dB RCS reduction from 9 to 40 GHz (126.5%) for normally TM- and TE- polarized incident waves. The good agreement between the simulation and measurement results at 0°, 20° and 40° incident angles prove the idea, also. The ultra wideband RCS reduction of the proposed metasurface as well as its low profile, light weight and low cost prove its high capability compared with the state of the art references.
Beneficial effects of murtilla extract and madecassic acid on insulin sensitivity and endothelial function in a model of diet-induced obesity
Authors: Arancibia-Radich Jorge , González-Blázquez Raquel , Alcalá Martín , Martín-Ramos Miriam , Viana Marta , Arribas Silvia , Delporte Carla , Fernández-Alfonso María S. , Somoza Beatriz , Gil-Ortega Marta
Published: January 2019

Infusions of murtilla leaves exhibit antioxidant, analgesic, and anti-inflammatory properties. Several compounds that are structurally similar to madecassic acid (MA), a component of murtilla leaf extract (ethyl acetate extract, EAE), have been shown to inhibit protein tyrosine phosphatase 1B (PTP1P). The aim of this study was to evaluate if EAE and two compounds identified in EAE (MA and myricetin [MYR]) could have a beneficial effect on systemic and vascular insulin sensitivity and endothelial function in a model of diet-induced obesity. Experiments were performed in 5-week-old male C57BL6J mice fed with a standard (LF) or a very high-fat diet (HF) for 4 weeks and treated with EAE, MA, MYR, or the vehicle as control (C). EAE significantly inhibited PTP1B. EAE and MA, but not MYR, significantly improved systemic insulin sensitivity in HF mice and vascular relaxation to Ach in aorta segments, due to a significant increase of eNOS phosphorylation and enhanced nitric oxide availability. EAE, MA, and MYR also accounted for increased relaxant responses to insulin in HF mice, thus evidencing that the treatments significantly improved aortic insulin sensitivity. This study shows for the first time that EAE and MA could constitute interesting candidates for treating insulin resistance and endothelial dysfunction associated with obesity.
Quantum-dot micropillar lasers subject to coherent time-delayed optical feedback from a short external cavity
Authors: Holzinger Steffen , Schneider Christian , Höfling Sven , Porte Xavier , Reitzenstein Stephan
Published: January 2019

We investigate the mode-switching dynamics of an electrically driven bimodal quantum-dot micropillar laser when subject to delayed coherent optical feedback from a short external cavity. We experimentally characterize how the external cavity length, being on the same order than the microlaser’s coherence length, influences the spectral and dynamical properties of the micropillar laser. Moreover, we determine the relaxation oscillation frequency of the micropillar by superimposing optical pulse injection to a dc current. It is found that the optical pulse can be used to disturb the feedback-coupled laser within one roundtrip time in such a way that it reaches the same output power as if no feedback was present. Our results do not only expand the understanding of microlasers when subject to optical feedback from short external cavities, but pave the way towards tailoring the properties of this key nanophotonic system for studies in the quantum regime of self-feedback and its implementation to integrated photonic circuits.
Dissipation of mesoscale eddies and its contribution to mixing in the northern South China Sea
Authors: Yang Qingxuan , Nikurashin Maxim , Sasaki Hideharu , Sun Hui , Tian Jiwei
Published: January 2019

It is reported that turbulent mixing is enhanced in the South China Sea (SCS), and it is highly variable in both space and time. Generation and breaking of internal tides has been identified as the main process to drive turbulent mixing in the SCS, while the contributions from other processes are not clear enough. Here we investigate the potential contribution from mesoscale eddies to turbulent mixing in the SCS using a high resolution numerical simulation. Our results show that mesoscale eddies in the SCS effectively dissipate over complex rough topography and indicate that the generation of submesoscale motions and lee waves are two pathways for the transfer of mesoscale eddy energy down to small dissipation scales. The energy loss from mesoscale eddies near the Xisha Islands is estimated to be sufficient to sustain turbulent kinetic energy dissipation rate of O (10−8) W/kg. This study suggests an alternative and potentially efficient mechanism to internal tides for the local maintenance of turbulent mixing in the SCS.
Near-field optical trapping in a non-conservative force field
Authors: Zaman Mohammad Asif , Padhy Punnag , Hesselink Lambertus
Published: January 2019

The force-field generated by a near-field optical trap is analyzed. A C-shaped engraving on a gold film is considered as the trap. By separating out the conservative component and the solenoidal component of the force-field using Helmholtz-Hodge decomposition, it was found that the force is non-conservative. Conventional method of calculating the optical potential from the force-field is shown to be inaccurate when the trapping force is not purely conservative. An alternative method is presented to accurately estimate the potential. The positional statistics of a trapped nanoparticle in this non-conservative field is calculated. A model is proposed that relates the position distribution to the conservative component of the force. The model is found to be consistent with numerical and experimental results. In order to show the generality of the approach, the same analysis is repeated for a plasmonic trap consisting of a gold nanopillar. Similar consistency is observed for this structure as well.
Gene target discovery with network analysis in Toxoplasma gondii
Authors: Alonso Andres M. , Corvi Maria M. , Diambra Luis
Published: January 2019

Infectious diseases are of great relevance for global health, but needed drugs and vaccines have not been developed yet or are not effective in many cases. In fact, traditional scientific approaches with intense focus on individual genes or proteins have not been successful in providing new treatments. Hence, innovations in technology and computational methods provide new tools to further understand complex biological systems such as pathogen biology. In this paper, we apply a gene regulatory network approach to analyze transcriptomic data of the parasite Toxoplasma gondii. By means of an optimization procedure, the phenotypic transitions between the stages associated with the life cycle of T. gondii were embedded into the dynamics of a gene regulatory network. Thus, through this methodology we were able to reconstruct a gene regulatory network able to emulate the life cycle of the pathogen. The community network analysis has revealed that nodes of the network can be organized in seven communities which allow us to assign putative functions to 338 previously uncharacterized genes, 25 of which are predicted as new pathogenic factors. Furthermore, we identified a small gene circuit that drives a series of phenotypic transitions that characterize the life cycle of this pathogen. These new findings can contribute to the understanding of parasite pathogenesis.
Rapid Oxidation of the Hole Transport Layer in Perovskite Solar Cells by A Low-Temperature Plasma
Authors: Wang Yumeng , Qu Hao , Zhang Chunmei , Chen Qiang
Published: January 2019

Herein we report a strategy of rapid oxidation of the hole transport layer (HTL) in perovskite solar cells by using oxygen/argon mixture plasma. This strategy offers a promising approach for simple manufacturing, mass production, and industrial applications. Compared to the conventional process of overnight oxidation, only ~10 s of oxygen/argon mixture plasma treatment is enough for the solar cell devices with FTO/ETL/perovskite/HTL/Au structure demonstrating a high power conversion efficiency. It is found that the high concentration of atomic oxygen generated in plasma oxidizing the HTL improves the conductivity and mobility, and therefore the process time is considerably shortened. This novel approach is compatible with continuous mass production, and it is suitable for the fabrication of large-area perovskite solar cells in the future.
Constructive approach for synthesis of a functional IgG using a reconstituted cell-free protein synthesis system
Authors: Murakami Satoshi , Matsumoto Rena , Kanamori Takashi
Published: January 2019

IgG is an indispensable biological experimental tool as well as a widely-used therapeutic protein. However, cell culture-based expression of monoclonal IgG is costly and time-consuming, making this process difficult to use for high-throughput screening in early-stage evaluation of biologics. With the goal of establishing a fast, simple, and robust high-throughput expression system for IgG, we implemented the synthesis of functional aglycosylated IgG by constructive approach based on a reconstituted prokaryotic cell-free protein synthesis system (PURE system). Optimization of the PURE system revealed that the following factors and reaction conditions were needed for IgG synthesis: (1) inclusion of the disulfide bond isomerase DsbC, (2) adjustment of the GSH/GSSG ratio, (3) inclusion of the molecular chaperone DnaK and its cofactors, and (4) use of an extended incubation time. Synthesis temperature and template DNA ratio (light chain-/heavy chain-encoding) also had been optimized for each IgG. Under optimal conditions, peak production of the anti-HER2 antibody trastuzumab reached 124 µg/mL. Furthermore, the active forms of other IgGs, including IgG1, IgG2, and IgG4 subclasses, also were synthesized. These results provide basic information for the development of novel high-throughput expression and functional screening systems for IgG, as well as useful information for understanding the IgG synthesis process.
Nebulized hypertonic saline triggers nervous system-mediated active liquid secretion in cystic fibrosis swine trachea
Authors: Luan Xiaojie , Tam Julian S. , Belev George , Jagadeeshan Santosh , Murray Brendan , Hassan Noman , Machen Terry E. , Chapman L. Dean , Ianowski Juan P.
Published: January 2019

Inhaled hypertonic saline (HTS) treatment is used to improve lung health in patients with cystic fibrosis (CF). The current consensus is that the treatment generates an osmotic gradient that draws water into the airways and increases airway surface liquid (ASL) volume. However, there is evidence that HTS may also stimulate active secretion of ASL by airway epithelia through the activation of sensory neurons. We tested the contribution of the nervous system and airway epithelia on HTS-stimulated ASL height increase in CF and wild-type swine airway. We used synchrotron-based imaging to investigate whether airway neurons and epithelia are involved in HTS treatment-triggered ASL secretion in CFTR−/− and wild-type swine. We showed that blocking parasympathetic and sensory neurons in airway resulted in ~50% reduction of the effect of HTS treatment on ASL volume in vivo. Incubating tracheal preparations with inhibitors of epithelial ion transport across airway decreased secretory responses to HTS treatment. CFTR−/− swine ex-vivo tracheal preparations showed substantially decreased secretory response to HTS treatment after blockage of neuronal activity. Our results indicated that HTS-triggered ASL secretion is partially mediated by the stimulation of airway neurons and the subsequent activation of active epithelia secretion; osmosis accounts for only ~50% of the effect.
pH Regulation and Tissue Coordination Pathways Promote Calcium Carbonate Bioerosion by Excavating Sponges
Authors: Webb Alice E. , Pomponi Shirley A. , van Duyl Fleur C. , Reichart Gert-Jan , de Nooijer Lennart J.
Published: January 2019

Coral reefs are threatened by a multitude of environmental and biotic influences. Among these, excavating sponges raise particular concern since they bore into coral skeleton forming extensive cavities which lead to weakening and loss of reef structures. Sponge bioerosion is achieved by a combination of chemical dissolution and mechanical chip removal and ocean acidification has been shown to accelerate bioerosion rates. However, despite the ecological relevance of sponge bioerosion, the exact chemical conditions in which dissolution takes place and how chips are removed remain elusive. Using fluorescence microscopy, we show that intracellular pH is lower at etching sites compared to ambient seawater and the sponge’s tissue. This is realised through the extension of filopodia filled with low intracellular pH vesicles suggesting that protons are actively transported into this microenvironment to promote CaCO3 dissolution. Furthermore, fusiform myocyte-like cells forming reticulated pathways were localised at the interface between calcite and sponge. Such cells may be used by sponges to contract a conductive pathway to remove chips possibly instigated by excess Ca2+ at the boring site. The mechanism underlying CaCO3 dissolution by sponges provides new insight into how environmental conditions can enhance dissolution and improves predictions of future rates of coral dissolution due to sponge activity.
Neuronal firing rates diverge during REM and homogenize during non-REM
Authors: Miyawaki Hiroyuki , Watson Brendon O. , Diba Kamran
Published: January 2019

Neurons fire at highly variable intrinsic rates and recent evidence suggests that low- and high-firing rate neurons display different plasticity and dynamics. Furthermore, recent publications imply possibly differing rate-dependent effects in hippocampus versus neocortex, but those analyses were carried out separately and with potentially important differences. To more effectively synthesize these questions, we analyzed the firing rate dynamics of populations of neurons in both hippocampal CA1 and frontal cortex under one framework that avoids the pitfalls of previous analyses and accounts for regression to the mean (RTM). We observed several consistent effects across these regions. While rapid eye movement (REM) sleep was marked by decreased hippocampal firing and increased neocortical firing, in both regions firing rate distributions widened during REM due to differential changes in high- versus low-firing rate cells in parallel with increased interneuron activity. In contrast, upon non-REM (NREM) sleep, firing rate distributions narrowed while interneuron firing decreased. Interestingly, hippocampal interneuron activity closely followed the patterns observed in neocortical principal cells rather than the hippocampal principal cells, suggestive of long-range interactions. Following these undulations in variance, the net effect of sleep was a decrease in firing rates. These decreases were greater in lower-firing hippocampal neurons but also higher-firing frontal cortical neurons, suggestive of greater plasticity in these cell groups. Our results across two different regions, and with statistical corrections, indicate that the hippocampus and neocortex show a mixture of differences and similarities as they cycle between sleep states with a unifying characteristic of homogenization of firing during NREM and diversification during REM.
A cationic near infrared fluorescent agent and ethyl-cinnamate tissue clearing protocol for vascular staining and imaging
Authors: Huang Jiaguo , Brenna Cinzia , Khan Arif ul Maula , Daniele Cristina , Rudolf Rüdiger , Heuveline Vincent , Gretz Norbert
Published: January 2019

Understanding vascular structures and dysfunction is a fundamental challenge. This task has been approached by using traditional methodologies such as microscopic computed tomography and magnetic resonance imaging. Both techniques are not only expensive but also time-consuming. Here, we present a new method for visualizing vascular structures in different organs in an efficient manner. A cationic near infrared (NIR) fluorescent dye was developed with attractive features to specifically stain blood vessels. Furthermore, we refined the process of organ staining and harvesting by retrograde perfusion and optimized the subsequent dehydration and clearing process by the use of an automatic tissue processor and a non-toxic substance, ethyl-cinnamate. Using this approach, the time interval between organ harvesting and microscopic analysis can be reduced from day(s) or weeks to 4 hours. Finally, we have demonstrated that the new NIR fluorescent agent in combination with confocal or light-sheet microscopy can be efficiently used for visualization of vascular structures, such as the blood vessels in different organs e.g. glomeruli in kidneys, with an extremely high resolution. Our approach facilitates the development of automatic image processing and the quantitative analysis to study vascular and kidney diseases.
The effects of drought and nutrient addition on soil organisms vary across taxonomic groups, but are constant across seasons
Authors: Siebert Julia , Sünnemann Marie , Auge Harald , Berger Sigrid , Cesarz Simone , Ciobanu Marcel , Guerrero-Ramírez Nathaly R. , Eisenhauer Nico
Published: January 2019

Anthropogenic global change alters the activity and functional composition of soil communities that are responsible for crucial ecosystem functions and services. Two of the most pervasive global change drivers are drought and nutrient enrichment. However, the responses of soil organisms to interacting global change drivers remain widely unknown. We tested the interactive effects of extreme drought and fertilization on soil biota ranging from microbes to invertebrates across seasons. We expected drought to reduce the activity of soil organisms and fertilization to induce positive bottom-up effects via increased plant productivity. Furthermore, we hypothesized fertilization to reinforce drought effects through enhanced plant growth, resulting in even drier soil conditions. Our results revealed that drought had detrimental effects on soil invertebrate feeding activity and simplified nematode community structure, whereas soil microbial activity and biomass were unaffected. Microbial biomass increased in response to fertilization, whereas invertebrate feeding activity substantially declined. Notably, these effects were consistent across seasons. The dissimilar responses suggest that soil biota differ vastly in their vulnerability to global change drivers. Thus, important ecosystem processes like decomposition and nutrient cycling, which are driven by the interdependent activity of soil microorganisms and invertebrates, may be disrupted under future conditions.
Tap water is one of the drivers that establish and assembly the lactic acid bacterium biota during sourdough preparation
Authors: Minervini Fabio , Dinardo Francesca Rita , De Angelis Maria , Gobbetti Marco
Published: January 2019

This study aimed at assessing the effect of tap water on the: (i) lactic acid bacteria (LAB) population of a traditional and mature sourdough; and (ii) establishment of LAB community during sourdough preparation. Ten tap water, collected from Italian regions characterized by cultural heritage in leavened baked goods, were used as ingredient for propagating or preparing firm (type I) sourdoughs. The same type and batch of flour, recipe, fermentation temperature and time were used for propagation/preparation, being water the only variable parameter. During nine days of propagation of a traditional and mature Apulian sourdough, LAB cell density did not differ, and the LAB species/strain composition hardly changed, regardless of the water. When the different tap water were used for preparing the corresponding sourdoughs, the values of pH became lower than 4.5 after two to four fermentations. The type of water affected the assembly of the LAB biome. As shown by Principal Components Analysis, LAB population in the sourdoughs and chemical and microbiological features of water used for their preparation partly overlapped. Several correlations were found between sourdough microbiota and water features. These data open the way to future researches about the use of various types of water in bakery industry.
Carbonic Anhydrase 6 Gene Variation influences Oral Microbiota Composition and Caries Risk in Swedish adolescents
Authors: Esberg A. , Haworth S. , Brunius C. , Lif Holgerson P. , Johansson I.
Published: January 2019

Carbonic anhydrase VI (CA6) catalyses the reversible hydration of carbon dioxide in saliva with possible pH regulation, taste perception, and tooth formation effects. This study assessed effects of variation in the CA6 gene on oral microbiota and specifically the acidophilic and caries-associated Streptococcus mutans in 17-year old Swedish adolescents (n = 154). Associations with caries status and secreted CA6 protein were also evaluated. Single Nucleotide Polymorphisms (27 SNPs in 5 haploblocks) and saliva and tooth biofilm microbiota from Illumina MiSeq 16S rDNA (V3-V4) sequencing and culturing were analysed. Haploblock 4 (rs10864376, rs3737665, rs12138897) CCC associated with low prevalence of S. mutans (OR (95% CI): 0.5 (0.3, 0.8)), and caries (OR 0.6 (0.3, 0.9)), whereas haploblock 4 TTG associated with high prevalence of S. mutans (OR: 2.7 (1.2, 5.9)) and caries (OR: 2.3 (1.2, 4.4)). The TTG-haploblock 4 (represented by rs12138897(G)) was characterized by S. mutans, Scardovia wiggsiae, Treponema sp. HOT268, Tannerella sp. HOT286, Veillonella gp.1 compared with the CCC-haploblock 4 (represented by rs12138897(C)). Secreted CA6 in saliva was weakly linked to CA6 gene variation. In conclusion, the results indicate that CA6 gene polymorphisms influence S. mutans colonization, tooth biofilm microbiota composition and risk of dental caries in Swedish adolescents.
Stem cell exosomes inhibit angiogenesis and tumor growth of oral squamous cell carcinoma
Authors: Rosenberger Leonie , Ezquer Marcelo , Lillo-Vera Fernando , Pedraza Paulina L. , Ortúzar María Ignacia , González Paz L. , Figueroa-Valdés Aliosha I. , Cuenca Jimena , Ezquer Fernando , Khoury Maroun , Alcayaga-Miranda Francisca
Published: January 2019

Recently, exosomes secreted by menstrual mesenchymal stem cells have been identified as inhibitory agents of tumor angiogenesis and modulators of the tumor cell secretome in prostate and breast cancer. However, their direct effect on endothelial cells and paracrine mediators have not yet been investigated. Using a carrier-based cell culture system to test the scalability for exosome production, we showed that different types of endothelial cells present specific kinetics for exosomes internalization. Exosome-treatment of endothelial cells increased cytotoxicity and reduced VEGF secretion and angiogenesis in a dose-dependent manner. Using the hamster buccal pouch carcinoma as a preclinical model for human oral squamous cell carcinoma, we demonstrated a significant antitumor effect of intra-tumoral injection of exosomes associated with a loss of tumor vasculature. These results address up-scaling of exosome production, a relevant issue for their clinical application, and also assess menstrual stem cell exosomes as potential anti-angiogenic agents for the treatment of neoplastic conditions.
Curcumin inhibits the TGF-β1-dependent differentiation of lung fibroblasts via PPARγ-driven upregulation of cathepsins B and L
Authors: Saidi Ahlame , Kasabova Mariana , Vanderlynden Lise , Wartenberg Mylène , Kara-Ali Ghania Hounana , Marc Daniel , Lecaille Fabien , Lalmanach Gilles
Published: January 2019

Pulmonary fibrosis is a progressive disease characterized by a widespread accumulation of myofibroblasts and extracellular matrix components. Growing evidences support that cysteine cathepsins, embracing cathepsin B (CatB) that affects TGF-β1-driven Smad pathway, along with their extracellular inhibitor cystatin C, participate in myofibrogenesis. Here we established that curcumin, a potent antifibrotic drug used in traditional Asian medicine, impaired the expression of both α-smooth muscle actin and mature TGF-β1 and inhibited the differentiation of human lung fibroblasts (CCD-19Lu cells). Curcumin induced a compelling upregulation of CatB and CatL. Conversely cystatin C was downregulated, which allowed the recovery of the peptidase activity of secreted cathepsins and the restoration of the proteolytic balance. Consistently, the amount of both insoluble and soluble type I collagen decreased, reaching levels similar to those observed for undifferentiated fibroblasts. The signaling pathways activated by curcumin were further examined. Curcumin triggered the expression of nuclear peroxisome proliferator-activated receptor γ (PPARγ). Contrariwise PPARγ inhibition, either by an antagonist (2-chloro-5-nitro-N-4-pyridinyl-benzamide) or by RNA silencing, restored TGF-β1-driven differentiation of curcumin-treated CCD-19Lu cells. PPARγ response element (PPRE)-like sequences were identified in the promoter regions of both CatB and CatL. Finally, we established that the transcriptional induction of CatB and CatL depends on the binding of PPARγ to PPRE sequences as a PPARγ/Retinoid X Receptor-α heterodimer.
Speed-Selectivity in Retinal Ganglion Cells is Sharpened by Broad Spatial Frequency, Naturalistic Stimuli
Authors: Ravello César R. , Perrinet Laurent U. , Escobar María-José , Palacios Adrián G.
Published: January 2019

Motion detection represents one of the critical tasks of the visual system and has motivated a large body of research. However, it remains unclear precisely why the response of retinal ganglion cells (RGCs) to simple artificial stimuli does not predict their response to complex, naturalistic stimuli. To explore this topic, we use Motion Clouds (MC), which are synthetic textures that preserve properties of natural images and are merely parameterized, in particular by modulating the spatiotemporal spectrum complexity of the stimulus by adjusting the frequency bandwidths. By stimulating the retina of the diurnal rodent, Octodon degus with MC we show that the RGCs respond to increasingly complex stimuli by narrowing their adjustment curves in response to movement. At the level of the population, complex stimuli produce a sparser code while preserving movement information; therefore, the stimuli are encoded more efficiently. Interestingly, these properties were observed throughout different populations of RGCs. Thus, our results reveal that the response at the level of RGCs is modulated by the naturalness of the stimulus - in particular for motion - which suggests that the tuning to the statistics of natural images already emerges at the level of the retina.
Stratification of amyotrophic lateral sclerosis patients: a crowdsourcing approach
Authors: Kueffner Robert , Zach Neta , Bronfeld Maya , Norel Raquel , Atassi Nazem , Balagurusamy Venkat , Di Camillo Barbara , Chio Adriano , Cudkowicz Merit , Dillenberger Donna , Garcia-Garcia Javier , Hardiman Orla , Hoff Bruce , Knight Joshua , Leitner Melanie L. , Li Guang , Mangravite Lara , Norman Thea , Wang Liuxia ,   The ALS Stratification Consortium, Alkallas Rached , Anghel Catalina , Avril Jeanne , Bacardit Jaume , Balser Barbara , Balser John , Bar-Sinai Yoav , Ben-David Noa , Ben-Zion Eyal , Bliss Robin , Cai Jialu , Chernyshev Anatoly , Chiang Jung-Hsien , Chicco Davide , Corriveau Bhavna Ahuja Nicole , Dai Junqiang , Deshpande Yash , Desplats Eve , Durgin Joseph S. , Espiritu Shadrielle Melijah G. , Fan Fan , Fevrier Philippe , Fridley Brooke L. , Godzik Adam , Golińska Agnieszka , Gordon Jonathan , Graw Stefan , Guo Yuelong , Herpelinck Tim , Hopkins Julia , Huang Barbara , Jacobsen Jeremy , Jahandideh Samad , Jeon Jouhyun , Ji Wenkai , Jung Kenneth , Karanevich Alex , Koestler Devin C. , Kozak Michael , Kurz Christoph , Lalansingh Christopher , Larrieu Thomas , Lazzarini Nicola , Lerner Boaz , Lesinski Wojciech , Liang Xiaotao , Lin Xihui , Lowe Jarrett , Mackey Lester , Meier Richard , Min Wenwen , Mnich Krzysztof , Nahmias Violette , Noel-MacDonnell Janelle , O’Donnell Adrienne , Paadre Susan , Park Ji , Polewko-Klim Aneta , Raghavan Rama , Rudnicki Witold , Saghapour Ehsan , Salomond Jean-Bernard , Sankaran Kris , Sendorek Dorota , Sharan Vatsal , Shiah Yu-Jia , Sirois Jean-Karl , Sumanaweera Dinithi N. , Usset Joseph , Vang Yeeleng S. , Vens Celine , Wadden Dave , Wang David , Wong Wing Chung , Xie Xiaohui , Xu Zhiqing , Yang Hsih-Te , Yu Xiang , Zhang Haichen , Zhang Li , Zhang Shihua , Zhu Shanfeng , Xiao Jinfeng , Fang Wen-Chieh , Peng Jian , Yang Chen , Chang Huan-Jui , Stolovitzky Gustavo
Published: January 2019

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease where substantial heterogeneity in clinical presentation urgently requires a better stratification of patients for the development of drug trials and clinical care. In this study we explored stratification through a crowdsourcing approach, the DREAM Prize4Life ALS Stratification Challenge. Using data from >10,000 patients from ALS clinical trials and 1479 patients from community-based patient registers, more than 30 teams developed new approaches for machine learning and clustering, outperforming the best current predictions of disease outcome. We propose a new method to integrate and analyze patient clusters across methods, showing a clear pattern of consistent and clinically relevant sub-groups of patients that also enabled the reliable classification of new patients. Our analyses reveal novel insights in ALS and describe for the first time the potential of a crowdsourcing to uncover hidden patient sub-populations, and to accelerate disease understanding and therapeutic development.
Improving orthotopic mouse models of patient-derived breast cancer brain metastases by a modified intracarotid injection method
Authors: Liu Zongming , Wang Yanzhi , Kabraji Sheheryar , Xie Shaozhen , Pan Peichen , Liu Zhenning , Ni Jing , Zhao Jean J.
Published: January 2019

Breast cancer brain metastasis (BCBM) remains a major clinical problem. Approximately 10–16% of patients with breast cancer develop brain metastases (BCBM). However, no systemic therapy has gained regulatory approval for the specific treatment of BCBM and this remains an area of persistent, unmet medical need. Rapid, predictive and clinically-relevant animal models are critical to study the biology of brain metastases and to identify effective therapeutic approaches for patients with BCBM. Here, we describe a method for efficient establishment of orthotopic mouse models of patient-derived brain metastases via an improved intracarotid injection protocol that permits tumor cell growth in the unique brain microenvironment without compromising the blood-brain barrier (BBB). We demonstrate that our newly improved models of patient-derived brain metastases recapitulate the histologic, molecular, and genetic characteristics of their matched patient tumor specimens and thus represent a potentially powerful tool for pre-clinical and translational research.
5-Fluorouracil Induces Enteric Neuron Death and Glial Activation During Intestinal Mucositis via a S100B-RAGE-NFκB-Dependent Pathway
Authors: Costa Deiziane V. S. , Bon-Frauches Ana C. , Silva Angeline M. H. P. , Lima-Júnior Roberto C. P. , Martins Conceição S. , Leitão Renata F. C. , Freitas Gutierrez B. , Castelucci Patricia , Bolick David T. , Guerrant Richard L. , Warren Cirle A. , Moura-Neto Vivaldo , Brito Gerly A. C.
Published: January 2019

5-Fluorouracil (5-FU) is an anticancer agent whose main side effects include intestinal mucositis associated with intestinal motility alterations maybe due to an effect on the enteric nervous system (ENS), but the underlying mechanism remains unclear. In this report, we used an animal model to investigate the participation of the S100B/RAGE/NFκB pathway in intestinal mucositis and enteric neurotoxicity caused by 5-FU (450 mg/kg, IP, single dose). 5-FU induced intestinal damage observed by shortened villi, loss of crypt architecture and intense inflammatory cell infiltrate as well as increased GFAP and S100B co-expression and decreased HuC/D protein expression in the small intestine. Furthermore, 5-FU increased RAGE and NFκB NLS immunostaining in enteric neurons, associated with a significant increase in the nitrite/nitrate, IL-6 and TNF-α levels, iNOS expression and MDA accumulation in the small intestine. We provide evidence that 5-FU induces reactive gliosis and reduction of enteric neurons in a S100B/RAGE/NFκB-dependent manner, since pentamidine, a S100B inhibitor, prevented 5-FU-induced neuronal loss, enteric glia activation, intestinal inflammation, oxidative stress and histological injury.
Incidental findings on brain MRI among Chinese at the age of 55–65 years: the Taizhou Imaging Study
Authors: Li Shuyuan , Fang Fang , Cui Mei , Jiang Yanfeng , Wang Yingzhe , Kong Xuhui , Tian Weizhong , Fan Min , Yuan Ziyu , Chen Jinhua , Yang Qi , Xue Fuzhong , Wang Jiucun , Lu Ming , Wang Xiaofeng , Chen Xingdong , Jin Li , Ye Weimin
Published: January 2019

Asymptomatic brain abnormalities are common incidental findings on brain MRI in the elderly population and can be regarded as imaging markers of early stroke and dementia. We initiated the Taizhou Imaging Study (TIS) to examine the prevalence and correlates of incidental findings using brain MRI among an elderly population residing in a rural area of China. A total of 562 individuals, at the age of 55 to 65 years, participated in the TIS study with a response rate of 90%. The prevalence of lacunes, white matter hyperintensity (WMH), cerebral microbleeds (CMB), perivascular space, and intracranial arterial stenosis was 26.69%, 10.68%, 18.51%, 27.76%, and 12.81%, respectively. Age and hypertension were the major correlates of these incidental findings. Per each year increase in age, the risks of WMH and CMB increased by 15% and 14%. Compared to individuals with normal blood pressure, individuals with hypertension had an increased risk of all incidental findings, with the adjusted odds ratios of 2.28 to 5.45. Correlations of age, gender and body mass index with brain gray matter fraction were also observed. The high prevalence of these findings indicates a need of preventative strategy to help prevent future stroke and dementia in this population.
Role of Water on the Rotational Dynamics of the Organic Methylammonium Cation: A First Principles Analysis
Authors: Hoehn Ross D. , Francisco Joseph S. , Kais Sabre , Kachmar Ali
Published: January 2019

Understanding the degradation mechanisms of lead-halide perovskites (CH3NH3PbI3) under exposure to liquid/aerosol water is an essential problem within the photovoltaic community. Herein we investigate both the static and the dynamic properties of the methylammonuim cation (MA) as it coordinates with invading water molecules (MA.(H2O)n, n = 1, 2, 3, 4) using both stationary state quantum mechanics and first principle molecular dynamics simulations. Various solvation structures of MA were characterized by their stabilization energies, dipoles, and Maximally-Localized Wannier Function (MLWF) centers. Calculation – and analysis – of vibrational shifts in the IR spectral region were performed for hydrated complexes; the locations of $${\bf{N}}{{\bf{H}}}_{{\bf{3}}}^{{\boldsymbol{+}}}$$
N

H

3

+

stretching vibrations allude to significant hydrogen bonding between MA and the water molecules. Through Fourier analysis of the rotational dynamics on several MA · (H2O)n complexes, we conclude that the water molecules dampen the rotational motion of the MA as the intermolecular bonds formed between the water molecules and the MA act to hinder the rotation of the cation; these findings give explanatory support to earlier computational observations of humidity effects on perovskites (i.e., CH3NH3PbI3) materials. This work is a step toward understanding the water-MA cation interaction in bulk perovskites, thus providing greater understanding of in situ instability/degradation of perovskite bulk materials.
Towards a Fishing Pressure Prediction System for a Western Pacific EEZ
Authors: Cimino Megan A. , Anderson Mark , Schramek Travis , Merrifield Sophia , Terrill Eric J.
Published: January 2019

Fisheries management faces numerous monitoring and enforcement challenges that are becoming more complex as fish stocks are depleted; and illegal, unregulated, and unreported fishing becomes more sophisticated. For remote island nations, the challenges are compounded by a loosely understood association of pelagic stocks to the ocean environment, and the tyranny of distance in monitoring and surveilling large exclusive economic zones (EEZ). An approach to ocean conservation is establishing protected areas, with the Pacific island nation of Palau as a leader with the recently established National Marine Sanctuary, which closes 80% of their EEZ to commercial fishing in 2020. Here we present an EEZ-wide analysis of Palau commercial fishing over a 6-year period (2011–2016), and develop a system for predicting fishing activity accounting for oceanic variables, climate indices, and vessel flag. Linking pelagic habitat to fishing activity provides high-resolution decision aids for management, highlighting the need for EEZ-specific analyses in addressing fisheries.
Influence of surface ocean density on planktonic foraminifera calcification
Authors: Zarkogiannis Stergios D. , Antonarakou Assimina , Tripati Aradhna , Kontakiotis George , Mortyn P. Graham , Drinia Hara , Greaves Mervyn
Published: January 2019

This study provides evidence that ambient seawater density influences calcification and may account for the observed planktonic foraminifera shell mass increase during glacial times. Volumes of weighed fossil Globigerina bulloides shells were accurately determined using X-ray Computer Tomography and were combined with water density reconstructions from Mg/Ca and δ18O measurements to estimate the buoyancy force exerted on each shell. After assessment of dissolution effects, the resulting relationship between shell mass and buoyancy suggests that heavier shells would need to be precipitated in glacial climates in order for these organisms to remain at their optimum living depth, and counterbalance the increased buoyant force of a denser, glacial ocean. Furthermore, the reanalysis of bibliographic data allowed the determination of a relationship between G. bulloides shell mass and ocean density, which introduces implications of a negative feedback mechanism for the uptake of atmospheric CO2 by the oceans.
Prominent action of butyrate over β-hydroxybutyrate as histone deacetylase inhibitor, transcriptional modulator and anti-inflammatory molecule
Authors: Chriett Sabrina , Dąbek Arkadiusz , Wojtala Martyna , Vidal Hubert , Balcerczyk Aneta , Pirola Luciano
Published: January 2019

Butyrate and R-β-hydroxybutyrate are two related short chain fatty acids naturally found in mammals. Butyrate, produced by enteric butyric bacteria, is present at millimolar concentrations in the gastrointestinal tract and at lower levels in blood; R-β-hydroxybutyrate, the main ketone body, produced by the liver during fasting can reach millimolar concentrations in the circulation. Both molecules have been shown to be histone deacetylase (HDAC) inhibitors, and their administration has been associated to an improved metabolic profile and better cellular oxidative status, with butyrate inducing PGC1α and fatty acid oxidation and R-β-hydroxybutyrate upregulating oxidative stress resistance factors FOXO3A and MT2 in mouse kidney. Because of the chemical and functional similarity between the two molecules, we compared here their impact on multiple cell types, evaluating i) histone acetylation and hydroxybutyrylation levels by immunoblotting, ii) transcriptional regulation of metabolic and inflammatory genes by quantitative PCR and iii) cytokine secretion profiles using proteome profiling array analysis. We confirm that butyrate is a strong HDAC inhibitor, a characteristic we could not identify in R-β-hydroxybutyrate in vivo nor in vitro. Butyrate had an extensive impact on gene transcription in rat myotubes, upregulating PGC1α, CPT1b, mitochondrial sirtuins (SIRT3-5), and the mitochondrial anti-oxidative genes SOD2 and catalase. In endothelial cells, butyrate suppressed gene expression and LPS-induced secretion of several pro-inflammatory genes, while R-β-hydroxybutyrate acted as a slightly pro-inflammatory molecule. Our observations indicate that butyrate induces transcriptional changes to a higher extent than R-β-hydroxybutyrate in rat myotubes and endothelial cells, in keep with its HDAC inhibitory activity. Also, in contrast with previous reports, R-β-hydroxybutyrate, while inducing histone β-hydroxybutyrylation, did not display a readily detectable HDAC inhibitor activity and exerted a slight pro-inflammatory action on endothelial cells.
Nucleotide-level Convolutional Neural Networks for Pre-miRNA Classification
Authors: Zheng Xueming , Xu Shungao , Zhang Ying , Huang Xinxiang
Published: January 2019

Due to the biogenesis difference, miRNAs can be divided into canonical microRNAs and mirtrons. Compared to canonical microRNAs, mirtrons are less conserved and hard to be identified. Except stringent annotations based on experiments, many in silico computational methods have be developed to classify miRNAs. Although several machine learning classifiers delivered high classification performance, all the predictors depended heavily on the selection of calculated features. Here, we introduced nucleotide-level convolutional neural networks (CNNs) for pre-miRNAs classification. By using “one-hot” encoding and padding, pre-miRNAs were converted into matrixes with the same shape. The convolution and max-pooling operations can automatically extract features from pre-miRNAs sequences. Evaluation on test dataset showed that our models had a satisfactory performance. Our investigation showed that it was feasible to apply CNNs to extract features from biological sequences. Since there are many hyperparameters can be tuned in CNNs, we believe that the performance of nucleotide-level convolutional neural networks can be greatly improved in the future.
Soluble urokinase plasminogen activation receptor and long-term outcomes in persons undergoing coronary angiography
Authors: Sommerer Claudia , Zeier Martin , Morath Christian , Reiser Jochen , Scharnagl Hubert , Stojakovic Tatjana , Delgado Graciela E. , März Winfried , Kleber Marcus E.
Published: January 2019

Soluble urokinase plasminogen activation receptor (suPAR) is risk factor for kidney disease and biomarker for cardiovascular outcomes but long term longitudinal analyses in a large European cohort have not been perfomed. To hus, we studied suPAR in participants of the Ludwigshafen Risk and Cardiovascular Health study over a very long follow-up time of nearly 10 years. We estimated overall risk of all-cause and cardiovascular death by Cox proportional hazards regression according to quartiles of suPAR, including age, sex, use of lipid-lowering drugs, body mass index, diabetes mellitus, hypertension, smoking, lipids, as well as glomerular filtration rate (eGFR), NT-proBNP, interleukin-6 and high-sensitive CRP as covariates. A total of 2940 participants (age 62.7 ± 10.5years) having a median eGFR of 83.8 mL/min/1.73 m2 were included. The median suPAR concentration was 3010 pg/mL (interquartile range, 2250–3988 pg/mL). Using the lowest quartile of suPAR as the reference, crude hazard ratio for cardiovascular mortality were 1.58 (95% CI 1.16–2.16), 1.85 (95% CI 1.37–2.52) and 2.75 (95% CI 2.03–3.71) in the second, third and fourth quartile, respectively. Adjusting for NT-proBNPeGFR or inflammation (interleukin-6 and high-sensitive CRP) confirmed results. suPAR predicts all-cause and cardiovascular death over a period of ten years in persons undergoing coronary angiography, independent of the natriuretic peptide NT-proBNP, kidney function and of markers of systemic inflammation. Future investigation into a potential causal role of suPAR in cardiovascular disease is warranted.
Process calculi may reveal the equivalence lying at the heart of RNA and proteins
Authors: Maestri Stefano , Merelli Emanuela
Published: January 2019

The successful use of process calculi to specify behavioural models allows us to compare RNA and protein folding processes from a new perspective. We model the folding processes as behaviours resulting from the interactions that nucleotides and amino acids (the elementary units that compose RNAs and proteins respectively) perform on their linear sequences. This approach is intended to provide new knowledge about the studied systems without strictly relying on empirical data. By applying Milner’s CCS process algebra to highlight the distinguishing features of the two folding processes, we discovered an abstraction level at which they show behavioural equivalences. We believe that this result could be interpreted as a clue in favour of the highly-debated RNA World theory, according to which, in the early stages of cell evolution, RNA molecules played most of the functional and structural roles carried out today by proteins.
Exploring the substrate scope of ferulic acid decarboxylase (FDC1) from Saccharomyces cerevisiae
Authors: Nagy Emma Zsófia Aletta , Nagy Csaba Levente , Filip Alina , Nagy Katalin , Gál Emese , Tőtős Róbert , Poppe László , Paizs Csaba , Bencze László Csaba
Published: January 2019

Ferulic acid decarboxylase fromSaccharomyces cerevisiae(ScFDC1) was described to possess a novel, prenylated flavin mononucleotide cofactor (prFMN) providing the first enzymatic 1,3-dipolar cycloaddition mechanism. The high tolerance of the enzyme towards several non-natural substrates, combined with its high quality, atomic resolution structure nominates FDC1 an ideal candidate as flexible biocatalyst for decarboxylation reactions leading to synthetically valuable styrenes. Herein the substrate scope ofScFDC1 is explored on substituted cinnamic acids bearing different functional groups (–OCH3, –CF3or –Br) at all positions of the phenyl ring (o−,m−,p−),as well as on several biaryl and heteroaryl cinnamic acid analogues or derivatives with extended alkyl chain. It was found thatE. coliwhole cells expressing recombinantScFDC1 could transform a large variety of substrates with high conversion, including several bulky aryl and heteroaryl cinnamic acid analogues, that characterizeScFDC1 as versatile and highly efficient biocatalyst. Computational studies revealed energetically favoured inactive binding positions and limited active site accessibility for bulky and non-linear substrates, such as 2-phenylthiazol-4-yl-, phenothiazine-2-yl- and 5-(4-bromophenyl)furan-2-yl) acrylic acids. In accordance with the computational predictions, site-directed mutagenesis of residue I330 provided variants with catalytic activity towards phenothiazine-2-yl acrylic acid and provides a basis for altering the substrate specificity of ScFDC1 by structure based rational design.