bluuebunny/crossref_metadata_2025 huggingface dataset:
The bacterium Wolbachia exploits host innate immunity to establish a symbiotic relationship with the dengue vector mosquito Aedes aegypti
Authors: Pan Xiaoling , Pike Andrew , Joshi Deepak , Bian Guowu , McFadden Michael J , Lu Peng , Liang Xiao , Zhang Fengrui , Raikhel Alexander S , Xi Zhiyong
Published: November 2017

A host’s immune system plays a central role in shaping the composition of the microbiota and, in return, resident microbes influence immune responses. Symbiotic associations of the maternally transmitted bacterium Wolbachia occur with a wide range of arthropods. It is, however, absent from the dengue and Zika vector mosquito Aedes aegypti in nature. When Wolbachia is artificially forced to form symbiosis with this new mosquito host, it boosts the basal immune response and enhances the mosquito’s resistance to pathogens, including dengue, Zika virus and malaria parasites. The mechanisms involved in establishing a symbiotic relationship between Wolbachia and A. aegypti, and the long-term outcomes of this interaction, are not well understood. Here, we have demonstrated that both the immune deficiency (IMD) and Toll pathways are activated by the Wolbachia strain wAlbB upon its introduction into A. aegypti. Silencing the Toll and IMD pathways via RNA interference reduces the wAlbB load. Notably, wAlbB induces peptidoglycan recognition protein (PGRP)-LE expression in the carcass of A. aegypti, and its silencing results in a reduction of symbiont load. Using transgenic mosquitoes with stage-specific induction of the IMD and Toll pathways, we have shown that elevated wAlbB infection in these mosquitoes is maintained via maternal transmission. These results indicate that host innate immunity is utilized to establish and promote host-microbial symbiosis. Our results will facilitate a long-term projection of the stability of the Wolbachia–A. aegypti mosquito system that is being developed to control dengue and Zika virus transmission to humans.
Re-designing Interleukin-12 to enhance its safety and potential as an anti-tumor immunotherapeutic agent
Authors: Wang Pengju , Li Xiaozhu , Wang Jiwei , Gao Dongling , Li Yuenan , Li Haoze , Chu Yongchao , Zhang Zhongxian , Liu Hongtao , Jiang Guozhong , Cheng Zhenguo , Wang Shengdian , Dong Jianzeng , Feng Baisui , Chard Louisa S. , Lemoine Nicholas R. , Wang Yaohe
Published: November 2017

Interleukin-12 (IL-12) has emerged as one of the most potent agents for anti-tumor immunotherapy. However, potentially lethal toxicity associated with systemic administration of IL-12 precludes its clinical application. Here we redesign the molecule in such a way that its anti-tumor efficacy is not compromised, but toxic effects are eliminated. Deletion of the N-terminal signal peptide of IL-12 can effect such a change by preventing IL-12 secretion from cells. We use a newly designed tumor-targeted oncolytic adenovirus (Ad-TD) to deliver non-secreting (ns) IL-12 to tumor cells and examine the therapeutic and toxic effects in Syrian hamster models of pancreatic cancer (PaCa). Strikingly, intraperitoneal delivery of Ad-TD-nsIL-12 significantly enhanced survival of animals with orthotopic PaCa and cured peritoneally disseminated PaCa with no toxic side effects, in contrast to the treatment with Ad-TD expressing unmodified IL-12. These findings offer renewed hope for development of IL-12-based treatments for cancer.
Effect of nitrogen atom positioning on the trade-off between emissive and photocatalytic properties of carbon dots
Authors: Bhattacharyya Santanu , Ehrat Florian , Urban Patrick , Teves Roland , Wyrwich Regina , Döblinger Markus , Feldmann Jochen , Urban Alexander S. , Stolarczyk Jacek K.
Published: November 2017

Carbon dots (CDs) are a versatile nanomaterial with attractive photoluminescent and photocatalytic properties. Here we show that these two functionalities can be easily tuned through a simple synthetic means, using a microwave irradiation, with citric acid and varying concentrations of nitrogen-containing branched polyethyleneimine (BPEI) as precursors. The amount of BPEI determines the degree of nitrogen incorporation and the different inclusion modes within the CDs. At intermediate levels of BPEI, domains grow containing mainly graphitic nitrogen, producing a high photoluminescence yield. For very high (and very low) BPEI content, the nitrogen atoms are located primarily at the edge sites of the aromatic domains. Accordingly, they attract photogenerated electrons, enabling efficient charge separation and enhanced photocatalytic hydrogen generation from water. The ensuing ability to switch between emissive and photocatalytic behavior of CDs is expected to bring substantial improvements on their efficiency for on-demand light emission or energy conversion applications.
Structural insights into DNA cleavage activation of CRISPR-Cas9 system
Authors: Huai Cong , Li Gan , Yao Ruijie , Zhang Yingyi , Cao Mi , Kong Liangliang , Jia Chenqiang , Yuan Hui , Chen Hongyan , Lu Daru , Huang Qiang
Published: November 2017

CRISPR-Cas9 technology has been widely used for genome engineering. Its RNA-guided endonuclease Cas9 binds specifically to target DNA and then cleaves the two DNA strands with HNH and RuvC nuclease domains. However, structural information regarding the DNA cleavage-activating state of two nuclease domains remains sparse. Here, we report a 5.2 Å cryo-EM structure of Cas9 in complex with sgRNA and target DNA. This structure reveals a conformational state of Cas9 in which the HNH domain is closest to the DNA cleavage site. Compared with two known HNH states, our structure shows that the HNH active site moves toward the cleavage site by about 25 and 13 Å, respectively. In combination with EM-based molecular dynamics simulations, we show that residues of the nuclease domains in our structure could form cleavage-compatible conformations with the target DNA. Together, these results strongly suggest that our cryo-EM structure resembles a DNA cleavage-activating architecture of Cas9.
Depleted depletion drives polymer swelling in poor solvent mixtures
Authors: Mukherji Debashish , Marques Carlos M. , Stuehn Torsten , Kremer Kurt
Published: November 2017

Establishing a link between macromolecular conformation and microscopic interaction is a key to understand properties of polymer solutions and for designing technologically relevant “smart” polymers. Here, polymer solvation in solvent mixtures strike as paradoxical phenomena. For example, when adding polymers to a solvent, such that all particle interactions are repulsive, polymer chains can collapse due to increased monomer–solvent repulsion. This depletion induced monomer–monomer attraction is well known from colloidal stability. A typical example is poly(methyl methacrylate) (PMMA) in water or small alcohols. While polymer collapse in a single poor solvent is well understood, the observed polymer swelling in mixtures of two repulsive solvents is surprising. By combining simulations and theoretical concepts known from polymer physics and colloidal science, we unveil the microscopic, generic origin of this collapse–swelling–collapse behavior. We show that this phenomenon naturally emerges at constant pressure when an appropriate balance of entropically driven depletion interactions is achieved.
Electromagnetic scattering laws in Weyl systems
Authors: Zhou Ming , Ying Lei , Lu Ling , Shi Lei , Zi Jian , Yu Zongfu
Published: November 2017

Wavelength determines the length scale of the cross section when electromagnetic waves are scattered by an electrically small object. The cross section diverges for resonant scattering, and diminishes for non-resonant scattering, when wavelength approaches infinity. This scattering law explains the colour of the sky as well as the strength of a mobile phone signal. We show that such wavelength scaling comes from the conical dispersion of free space at zero frequency. Emerging Weyl systems, offering similar dispersion at non-zero frequencies, lead to new laws of electromagnetic scattering that allow cross sections to be decoupled from the wavelength limit. Diverging and diminishing cross sections can be realized at any target wavelength in a Weyl system, providing the ability to tailor the strength of wave–matter interactions for radiofrequency and optical applications.
The self-healing of defects induced by the hydriding phase transformation in palladium nanoparticles
Authors: Ulvestad A. , Yau A.
Published: November 2017

Nanosizing can dramatically alter material properties by enhancing surface thermodynamic contributions, shortening diffusion lengths, and increasing the number of catalytically active sites per unit volume. These mechanisms have been used to explain the improved properties of catalysts, battery materials, plasmonic materials, etc. Here we show that Pd nanoparticles also have the ability to self-heal defects in their crystal structures. Using Bragg coherent diffractive imaging, we image dislocations nucleated deep in a Pd nanoparticle during the forward hydriding phase transformation that heal during the reverse transformation, despite the region surrounding the dislocations remaining in the hydrogen-poor phase. We show that defective Pd nanoparticles exhibit sloped isotherms, indicating that defects act as additional barriers to the phase transformation. Our results resolve the formation and healing of structural defects during phase transformations at the single nanoparticle level and offer an additional perspective as to how and why nanoparticles differ from their bulk counterparts.
A water-soluble nucleolin aptamer-paclitaxel conjugate for tumor-specific targeting in ovarian cancer
Authors: Li Fangfei , Lu Jun , Liu Jin , Liang Chao , Wang Maolin , Wang Luyao , Li Defang , Yao Houzong , Zhang Qiulong , Wen Jia , Zhang Zong-Kang , Li Jie , Lv Quanxia , He Xiaojuan , Guo Baosheng , Guan Daogang , Yu Yuanyuan , Dang Lei , Wu Xiaohao , Li Yongshu , Chen Guofen , Jiang Feng , Sun Shiguo , Zhang Bao-Ting , Lu Aiping , Zhang Ge
Published: November 2017

Paclitaxel (PTX) is among the most commonly used first-line drugs for cancer chemotherapy. However, its poor water solubility and indiscriminate distribution in normal tissues remain clinical challenges. Here we design and synthesize a highly water-soluble nucleolin aptamer-paclitaxel conjugate (NucA-PTX) that selectively delivers PTX to the tumor site. By connecting a tumor-targeting nucleolin aptamer (NucA) to the active hydroxyl group at 2′ position of PTX via a cathepsin B sensitive dipeptide bond, NucA-PTX remains stable and inactive in the circulation. NucA facilitates the uptake of the conjugated PTX specifically in tumor cells. Once inside cells, the dipeptide bond linker of NucA-PTX is cleaved by cathepsin B and then the conjugated PTX is released for action. The NucA modification assists the selective accumulation of the conjugated PTX in ovarian tumor tissue rather than normal tissues, and subsequently resulting in notably improved antitumor activity and reduced toxicity.
Impacts of hemispheric solar geoengineering on tropical cyclone frequency
Authors: Jones Anthony C. , Haywood James M. , Dunstone Nick , Emanuel Kerry , Hawcroft Matthew K. , Hodges Kevin I. , Jones Andy
Published: November 2017

Solar geoengineering refers to a range of proposed methods for counteracting global warming by artificially reducing sunlight at Earth’s surface. The most widely known solar geoengineering proposal is stratospheric aerosol injection (SAI), which has impacts analogous to those from volcanic eruptions. Observations following major volcanic eruptions indicate that aerosol enhancements confined to a single hemisphere effectively modulate North Atlantic tropical cyclone (TC) activity in the following years. Here we investigate the effects of both single-hemisphere and global SAI scenarios on North Atlantic TC activity using the HadGEM2-ES general circulation model and various TC identification methods. We show that a robust result from all of the methods is that SAI applied to the southern hemisphere would enhance TC frequency relative to a global SAI application, and vice versa for SAI in the northern hemisphere. Our results reemphasise concerns regarding regional geoengineering and should motivate policymakers to regulate large-scale unilateral geoengineering deployments.
AIP limits neurotransmitter release by inhibiting calcium bursts from the ryanodine receptor
Authors: Chen Bojun , Liu Ping , Hujber Edward J. , Li Yan , Jorgensen Erik M. , Wang Zhao-Wen
Published: November 2017

Pituitary tumors are frequently associated with mutations in the AIP gene and are sometimes associated with hypersecretion of growth hormone. It is unclear whether other factors besides an enlarged pituitary contribute to the hypersecretion. In a genetic screen for suppressors of reduced neurotransmitter release, we identified a mutation in Caenorhabditis elegans AIPR-1 (AIP-related-1), which causes profound increases in evoked and spontaneous neurotransmitter release, a high frequency of spontaneous calcium transients in motor neurons and an enlarged readily releasable pool of vesicles. Calcium bursts and hypersecretion are reversed by mutations in the ryanodine receptor but not in the voltage-gated calcium channel, indicating that these phenotypes are caused by a leaky ryanodine receptor. AIPR-1 is physically associated with the ryanodine receptor at synapses. Finally, the phenotypes in aipr-1 mutants can be rescued by presynaptic expression of mouse AIP, demonstrating that a conserved function of AIP proteins is to inhibit calcium release from ryanodine receptors.
Integrated radiomic framework for breast cancer and tumor biology using advanced machine learning and multiparametric MRI
Authors: Parekh Vishwa S. , Jacobs Michael A.
Published: November 2017

Radiomics deals with the high throughput extraction of quantitative textural information from radiological images that not visually perceivable by radiologists. However, the biological correlation between radiomic features and different tissues of interest has not been established. To that end, we present the radiomic feature mapping framework to generate radiomic MRI texture image representations called the radiomic feature maps (RFM) and correlate the RFMs with quantitative texture values, breast tissue biology using quantitative MRI and classify benign from malignant tumors. We tested our radiomic feature mapping framework on a retrospective cohort of 124 patients (26 benign and 98 malignant) who underwent multiparametric breast MR imaging at 3 T. The MRI parameters used were T1-weighted imaging, T2-weighted imaging, dynamic contrast enhanced MRI (DCE-MRI) and diffusion weighted imaging (DWI). The RFMs were computed by convolving MRI images with statistical filters based on first order statistics and gray level co-occurrence matrix features. Malignant lesions demonstrated significantly higher entropy on both post contrast DCE-MRI (Benign-DCE entropy: 5.72 ± 0.12, Malignant-DCE entropy: 6.29 ± 0.06, p = 0.0002) and apparent diffusion coefficient (ADC) maps as compared to benign lesions (Benign-ADC entropy: 5.65 ± 0.15, Malignant ADC entropy: 6.20 ± 0.07, p = 0.002). There was no significant difference between glandular tissue entropy values in the two groups. Furthermore, the RFMs from DCE-MRI and DWI demonstrated significantly different RFM curves for benign and malignant lesions indicating their correlation to tumor vascular and cellular heterogeneity respectively. There were significant differences in the quantitative MRI metrics of ADC and perfusion. The multiview IsoSVM model classified benign and malignant breast tumors with sensitivity and specificity of 93 and 85%, respectively, with an AUC of 0.91.
A bacterial pioneer produces cellulase complexes that persist through community succession
Authors: Kolinko Sebastian , Wu Yu-Wei , Tachea Firehiwot , Denzel Evelyn , Hiras Jennifer , Gabriel Raphael , Bäcker Nora , Chan Leanne Jade G. , Eichorst Stephanie A. , Frey Dario , Chen Qiushi , Azadi Parastoo , Adams Paul D. , Pray Todd R. , Tanjore Deepti , Petzold Christopher J. , Gladden John M. , Simmons Blake A. , Singer Steven W.
Published: November 2017

Cultivation of microbial consortia provides low-complexity communities that can serve as tractable models to understand community dynamics. Time-resolved metagenomics demonstrated that an aerobic cellulolytic consortium cultivated from compost exhibited community dynamics consistent with the definition of an endogenous heterotrophic succession. The genome of the proposed pioneer population, ‘Candidatus Reconcilibacillus cellulovorans’, possessed a gene cluster containing multidomain glycoside hydrolases (GHs). Purification of the soluble cellulase activity from a 300litre cultivation of this consortium revealed that ~70% of the activity arose from the ‘Ca. Reconcilibacillus cellulovorans’ multidomain GHs assembled into cellulase complexes through glycosylation. These remarkably stable complexes have supramolecular structures for enzymatic cellulose hydrolysis that are distinct from cellulosomes. The persistence of these complexes during cultivation indicates that they may be active through multiple cultivations of this consortium and act as public goods that sustain the community. The provision of extracellular GHs as public goods may influence microbial community dynamics in native biomass-deconstructing communities relevant to agriculture, human health and biotechnology.
Supernatural Belief Is Not Modulated by Intuitive Thinking Style or Cognitive Inhibition
Authors: Farias Miguel , van Mulukom Valerie , Kahane Guy , Kreplin Ute , Joyce Anna , Soares Pedro , Oviedo Lluis , Hernu Mathilde , Rokita Karolina , Savulescu Julian , Möttönen Riikka
Published: November 2017

According to the Intuitive Belief Hypothesis, supernatural belief relies heavily on intuitive thinking—and decreases when analytic thinking is engaged. After pointing out various limitations in prior attempts to support this Intuitive Belief Hypothesis, we test it across three new studies using a variety of paradigms, ranging from a pilgrimage field study to a neurostimulation experiment. In all three studies, we found no relationship between intuitive or analytical thinking and supernatural belief. We conclude that it is premature to explain belief in gods as ‘intuitive’, and that other factors, such as socio-cultural upbringing, are likely to play a greater role in the emergence and maintenance of supernatural belief than cognitive style.
TALEN-mediated functional correction of human iPSC-derived macrophages in context of hereditary pulmonary alveolar proteinosis
Authors: Kuhn Alexandra , Ackermann Mania , Mussolino Claudio , Cathomen Toni , Lachmann Nico , Moritz Thomas
Published: November 2017

Hereditary pulmonary alveolar proteinosis (herPAP) constitutes a rare, life threatening lung disease characterized by the inability of alveolar macrophages to clear the alveolar airspaces from surfactant phospholipids. On a molecular level, the disorder is defined by a defect in the CSF2RA gene coding for the GM-CSF receptor alpha-chain (CD116). As therapeutic options are limited, we currently pursue a cell and gene therapy approach aiming for the intrapulmonary transplantation of gene-corrected macrophages derived from herPAP-specific induced pluripotent stem cells (herPAP-iPSC) employing transcriptional activator-like effector nucleases (TALENs). Targeted insertion of a codon-optimized CSF2RA-cDNA driven by the hybrid cytomegalovirus (CMV) early enhancer/chicken beta actin (CAG) promoter into the AAVS1 locus resulted in robust expression of the CSF2RA gene in gene-edited herPAP-iPSCs as well as thereof derived macrophages. These macrophages displayed typical morphology, surface phenotype, phagocytic and secretory activity, as well as functional CSF2RA expression verified by STAT5 phosphorylation and GM-CSF uptake studies. Thus, our study provides a proof-of-concept, that TALEN-mediated integration of the CSF2RA gene into the AAVS1 safe harbor locus in patient-specific iPSCs represents an efficient strategy to generate functionally corrected monocytes/macrophages, which in the future may serve as a source for an autologous cell-based gene therapy for the treatment of herPAP.
Visualization and quantification of injury to the ciliated epithelium using quantitative flow imaging and speckle variance optical coherence tomography
Authors: Gamm Ute A. , Huang Brendan K. , Mis Emily K. , Khokha Mustafa K. , Choma Michael A.
Published: November 2017

Mucociliary flow is an important defense mechanism in the lung to remove inhaled pathogens and pollutants. Disruption of ciliary flow can lead to respiratory infections. Multiple factors, from drugs to disease can cause an alteration in ciliary flow. However, less attention has been given to injury of the ciliated epithelium. In this study, we show how optical coherence tomography (OCT) can be used to investigate injury to the ciliated epithelium in a multi-contrast setting. We used particle tracking velocimetry (PTV-OCT) to investigate the cilia-driven flow field and 3D speckle variance imaging to investigate size and extent of injury caused to the skin of Xenopus embryos. Two types of injuries are investigated, focal injury caused by mechanical damage and diffuse injury by a calcium chloride shock. We additionally investigate injury and regeneration of cilia to calcium chloride on ex vivo mouse trachea. This work describes how OCT can be used as a tool to investigate injury and regeneration in ciliated epithelium.
Universal glass-forming behavior of in vitro and living cytoplasm
Authors: Nishizawa Kenji , Fujiwara Kei , Ikenaga Masahiro , Nakajo Nobushige , Yanagisawa Miho , Mizuno Daisuke
Published: November 2017

Physiological processes in cells are performed efficiently without getting jammed although cytoplasm is highly crowded with various macromolecules. Elucidating the physical machinery is challenging because the interior of a cell is so complex and driven far from equilibrium by metabolic activities. Here, we studied the mechanics of in vitro and living cytoplasm using the particle-tracking and manipulation technique. The molecular crowding effect on cytoplasmic mechanics was selectively studied by preparing simple in vitro models of cytoplasm from which both the metabolism and cytoskeletons were removed. We obtained direct evidence of the cytoplasmic glass transition; a dramatic increase in viscosity upon crowding quantitatively conformed to the super-Arrhenius formula, which is typical for fragile colloidal suspensions close to jamming. Furthermore, the glass-forming behaviors were found to be universally conserved in all the cytoplasm samples that originated from different species and developmental stages; they showed the same tendency for diverging at the macromolecule concentrations relevant for living cells. Notably, such fragile behavior disappeared in metabolically active living cells whose viscosity showed a genuine Arrhenius increase as in typical strong glass formers. Being actively driven by metabolism, the living cytoplasm forms glass that is fundamentally different from that of its non-living counterpart.
Publisher Correction: Atomic-scale engineering of ferroelectric-ferromagnetic interfaces of epitaxial perovskite films for functional properties
Authors: Hausmann Simon , Ye Jingfan , Aoki Toshihiro , Zheng Jian-Guo , Stahn Jochen , Bern Francis , Chen Binda , Autieri Carmine , Sanyal Biplab , Esquinazi Pablo D. , Böni Peter , Paul Amitesh
Published: November 2017

A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.
Divergent proliferation patterns of distinct human hair follicle epithelial progenitor niches in situ and their differential responsiveness to prostaglandin D2
Authors: Purba Talveen S. , Peake Michael , Farjo Bessam , Farjo Nilofer , Bhogal Ranjit K. , Jenkins Gail , Paus Ralf
Published: November 2017

Human scalp hair follicles (hHF) harbour several epithelial stem (eHFSC) and progenitor cell sub-populations organised into spatially distinct niches. However, the constitutive cell cycle activity of these niches remains to be characterized in situ. Therefore, the current study has studied these characteristics of keratin 15+ (K15), CD200+ or CD34+ cells within anagen VI hHFs by immunohistomorphometry, using Ki-67 and 5-ethynyl-2′-deoxyuridine (EdU). We quantitatively demonstrate in situ the relative cell cycle inactivity of the CD200+/K15+ bulge compared to other non-bulge CD34+ and K15+ progenitor compartments and found that in each recognized eHFSC/progenitor niche, proliferation associates negatively with eHFSC-marker expression. Furthermore, we also show how prostaglandin D2 (PGD2), which is upregulated in balding scalp, differentially impacts on the proliferation of distinct eHFSC populations. Namely, 24 h organ-cultured hHFs treated with PGD2 displayed reduced Ki-67 expression and EdU incorporation in bulge resident K15+ cells, but not in supra/proximal bulb outer root sheath K15+ progenitors. This study emphasises clear differences between the cell cycle behaviour of spatially distinct stem/progenitor cell niches in the hHF, and demonstrates a possible link between PGD2 and perturbed proliferation dynamics in epithelial stem cells.
Global mapping of stratigraphy of an old-master painting using sparsity-based terahertz reflectometry
Authors: Dong Junliang , Locquet Alexandre , Melis Marcello , Citrin D. S.
Published: November 2017

The process by which art paintings are produced typically involves the successive applications of preparatory and paint layers to a canvas or other support; however, there is an absence of nondestructive modalities to provide a global mapping of the stratigraphy, information that is crucial for evaluation of its authenticity and attribution, for insights into historical or artist-specific techniques, as well as for conservation. We demonstrate sparsity-based terahertz reflectometry can be applied to extract a detailed 3D mapping of the layer structure of the 17th century easel painting Madonna in Preghiera by the workshop of Giovanni Battista Salvi da Sassoferrato, in which the structure of the canvas support, the ground, imprimatura, underpainting, pictorial, and varnish layers are identified quantitatively. In addition, a hitherto unidentified restoration of the varnish has been found. Our approach unlocks the full promise of terahertz reflectometry to provide a global and detailed account of an easel painting’s stratigraphy by exploiting the sparse deconvolution, without which terahertz reflectometry in the past has only provided a meager tool for the characterization of paintings with paint-layer thicknesses smaller than 50 μm. The proposed modality can also be employed across a broad range of applications in nondestructive testing and biomedical imaging.
Zinc is a critical regulator of placental morphogenesis and maternal hemodynamics during pregnancy in mice
Authors: Wilson Rebecca L. , Leemaqz Shalem Y. , Goh Zona , McAninch Dale , Jankovic-Karasoulos Tanja , Leghi Gabriela E. , Phillips Jessica A. , Colafella Katrina Mirabito , Tran Cuong , O’Leary Sean , Buckberry Sam , Pederson Stephen , Robertson Sarah A. , Bianco-Miotto Tina , Roberts Claire T.
Published: November 2017

Zinc is an essential micronutrient in pregnancy and zinc deficiency impairs fetal growth. We used a mouse model of moderate zinc deficiency to investigate the physiological mechanisms by which zinc is important to placental morphogenesis and the maternal blood pressure changes during pregnancy. A 26% reduction in circulating zinc (P = 0.005) was exhibited in mice fed a moderately zinc-deficient diet. Zinc deficiency in pregnancy resulted in an 8% reduction in both near term fetal and placental weights (both P < 0.0001) indicative of disrupted placental development and function. Detailed morphological analysis confirmed changes to the placental labyrinth microstructure. Continuous monitoring of maternal mean arterial pressure (MAP) revealed a late gestation decrease in the zinc-deficient dams. Differential expression of a number of regulatory genes within maternal kidneys supported observations on MAP changes in gestation. Increased MAP late in gestation is required to maintain perfusion of multiple placentas within rodent pregnancies. Decreased MAP within the zinc-deficient dams implies reduced blood flow and nutrient delivery to the placenta. These findings show that adequate zinc status is required for correct placental morphogenesis and appropriate maternal blood pressure adaptations to pregnancy. We conclude that insufficient maternal zinc intake from before and during pregnancy is likely to impact in utero programming of offspring growth and development largely through effects to the placenta and maternal cardiovascular system.
Identification of a novel cAMP dependent protein kinase A phosphorylation site on the human cardiac calcium channel
Authors: Cserne Szappanos Henrietta , Muralidharan Padmapriya , Ingley Evan , Petereit Jakob , Millar A. Harvey , Hool Livia C.
Published: November 2017

The “Fight or Flight” response is elicited by extrinsic stress and is necessary in many species for survival. The response involves activation of the β-adrenergic signalling pathway. Surprisingly the mechanisms have remained unresolved. Calcium influx through the cardiac L-type Ca2+ channel (Cav1.2) is absolutely required. Here we identify the functionally relevant site for PKA phosphorylation on the human cardiac L-type Ca2+ channel pore forming α1 subunit using a novel approach. We used a cell free system where we could assess direct effects of PKA on human purified channel protein function reconstituted in proteoliposomes. In addition to assessing open probability of channel protein we used semi-quantitative fluorescent phosphoprotein detection and MS/MS mass spectrometry analysis to demonstrate the PKA specificity of the site. Robust increases in frequency of channel openings were recorded after phosphorylation of the long and short N terminal isoforms and the channel protein with C terminus truncated at aa1504. A protein kinase A anchoring protein (AKAP) was not required. We find the novel PKA phosphorylation site at Ser1458 is in close proximity to the Repeat IV S6 region and induces a conformational change in the channel protein that is necessary and sufficient for increased calcium influx through the channel.
Rupturing Giant Plasma Membrane Vesicles to Form Micron-sized Supported Cell Plasma Membranes with Native Transmembrane Proteins
Authors: Chiang Po-Chieh , Tanady Kevin , Huang Ling-Ting , Chao Ling
Published: November 2017

Being able to directly obtain micron-sized cell blebs, giant plasma membrane vesicles (GPMVs), with native membrane proteins and deposit them on a planar support to form supported plasma membranes could allow the membrane proteins to be studied by various surface analytical tools in native-like bilayer environments. However, GPMVs do not easily rupture on conventional supports because of their high protein and cholesterol contents. Here, we demonstrate the possibility of using compression generated by the air-water interface to efficiently rupture GPMVs to form micron-sized supported membranes with native plasma membrane proteins. We demonstrated that not only lipid but also a native transmembrane protein in HeLa cells, Aquaporin 3 (AQP3), is mobile in the supported membrane platform. This convenient method for generating micron-sized supported membrane patches with mobile native transmembrane proteins could not only facilitate the study of membrane proteins by surface analytical tools, but could also enable us to use native membrane proteins for bio-sensing applications.
Genomic and epidemiological characterisation of a dengue virus outbreak among blood donors in Brazil
Authors: Faria Nuno R. , da Costa Antonio Charlys , Lourenço José , Loureiro Paula , Lopes Maria Esther , Ribeiro Roberto , Alencar Cecilia Salete , Kraemer Moritz U. G. , Villabona-Arenas Christian J. , Wu Chieh-Hsi , Thézé Julien , Khan Kamran , Brent Shannon E. , Romano Camila , Delwart Eric , Custer Brian , Busch Michael P. , Pybus Oliver G. , Sabino Ester C. ,   NHLBI Recipient Epidemiology and Donor Evaluation Study-III (REDS-III), Neto Cesar de Almeida , Mendrone-Junior Alfredo , Bárbara Carneiro-Proietti Anna , Sampaio Divaldo de Almeida , Lobo Clarisse , Capuani Ligia , Ferreira João Eduardo , Oikawa Marcio , Losco Takecian Pedro , Oliveira Cláudia Di Lorenzo , Kelly Shannon , Gonçalez Thelma T. , Brambilla Donald , McClure Christopher , Glynn Simone A.
Published: November 2017

Outbreaks caused by Dengue, Zika and Chikungunya viruses can spread rapidly in immunologically naïve populations. By analysing 92 newly generated viral genome sequences from blood donors and recipients, we assess the dynamics of dengue virus serotype 4 during the 2012 outbreak in Rio de Janeiro. Phylogenetic analysis indicates that the outbreak was caused by genotype II, although two isolates of genotype I were also detected for the first time in Rio de Janeiro. Evolutionary analysis and modelling estimates are congruent, indicating a reproduction number above 1 between January and June, and at least two thirds of infections being unnoticed. Modelling analysis suggests that viral transmission started in early January, which is consistent with multiple introductions, most likely from the northern states of Brazil, and with an increase in within-country air travel to Rio de Janeiro. The combination of genetic and epidemiological data from blood donor banks may be useful to anticipate epidemic spread of arboviruses.
Association of long noncoding RNAs expression levels and their gene polymorphisms with systemic lupus erythematosus
Authors: Li Jun , Wu Guo-Cui , Zhang Tian-Ping , Yang Xiao-Ke , Chen Shuang-Shuang , Li Lian-Ju , Xu Shu-Zhen , Lv Tian-Tian , Leng Rui-Xue , Pan Hai-Feng , Ye Dong-Qing
Published: November 2017

Increasing evidence has demonstrated the association between long noncoding RNAs (lncRNAs) and multiple autoimmune diseases. To explore four lncRNAs (GAS5, lnc-DC, linc0597 and linc0949) expression levels and gene polymorphisms in systemic lupus erythematosus (SLE), a two stage design was applied. In the first stage, 85 SLE patients and 71 healthy controls were enrolled to investigate the lncRNAs expression levels. Then, 1260 SLE patients and 1231 healthy controls were included to detect the single nucleotide polymorphisms (SNPs) in the differentially expressed lncRNAs identified in the first stage. Linc0597, lnc-DC and GAS5 expression levels were significantly lower in SLE patients than healthy controls (P < 0.001, P < 0.001, P = 0.003 respectively). Association of five SNPs (rs10515177, rs2070107, rs2632516, rs2877877, rs2067079) with SLE risk were analyzed. No significant association was observed between these gene polymorphisms and susceptibility to SLE (all P > 0.010), and we did not find significant association between any genotypes at five SNPs and their respective lncRNAs expression in SLE (all P > 0.010). In summary, the expression levels of linc0597, lnc-DC and GAS5 are decreased in SLE patients, but their gene polymorphisms are not associated with SLE risk, and do not influence their expression levels.
ADAM9 promotes lung cancer progression through vascular remodeling by VEGFA, ANGPT2, and PLAT
Authors: Lin Chen-Yuan , Cho Chia-Fong , Bai Shih-Ting , Liu Jing-Pei , Kuo Ting-Ting , Wang Li-Ju , Lin Yu-Sen , Lin Ching-Chan , Lai Liang-Chuan , Lu Tzu-Pin , Hsieh Chih-Ying , Chu Chin-Nan , Cheng Da-Chuan , Sher Yuh-Pyng
Published: November 2017

Lung cancer has a very high prevalence of brain metastasis, which results in a poor clinical outcome. Up-regulation of a disintegrin and metalloproteinase 9 (ADAM9) in lung cancer cells is correlated with metastasis to the brain. However, the molecular mechanism underlying this correlation remains to be elucidated. Since angiogenesis is an essential step for brain metastasis, microarray experiments were used to explore ADAM9-regulated genes that function in vascular remodeling. The results showed that the expression levels of vascular endothelial growth factor A (VEGFA), angiopoietin-2 (ANGPT2), and tissue plasminogen activator (PLAT) were suppressed in ADAM9-silenced cells, which in turn leads to decreases in angiogenesis, vascular remodeling, and tumor growth in vivo. Furthermore, simultaneous high expression of ADAM9 and VEGFA or of ADAM9 and ANGPT2 was correlated with poor prognosis in a clinical dataset. These findings suggest that ADAM9 promotes tumorigenesis through vascular remodeling, particularly by increasing the function of VEGFA, ANGPT2, and PLAT.
Effects of atomic-level nano-structured hydroxyapatite on adsorption of bone morphogenetic protein-7 and its derived peptide by computer simulation
Authors: Wang Qun , Wang Menghao , Lu Xiong , Wang Kefeng , Fang Liming , Ren Fuzeng , Lu Guoming
Published: November 2017

Hydroxyapatite (HA) is the principal inorganic component of bones and teeth and has been widely used as a bone repair material because of its good biocompatibility and bioactivity. Understanding the interactions between proteins and HA is crucial for designing biomaterials for bone regeneration. In this study, we evaluated the effects of atomic-level nano-structured HA (110) surfaces on the adsorption of bone morphogenetic protein-7 (BMP-7) and its derived peptide (KQLNALSVLYFDD) using molecular dynamics and density functional theory methods. The results indicated that the atomic-level morphology of HA significantly affected the interaction strength between proteins and HA substrates. The interactions of BMP-7 and its derived peptide with nano-concave and nano-pillar HA surfaces were stronger than those with flat or nano-groove HA surfaces. The results also revealed that if the groove size of nano-structured HA surfaces matched that of residues in the protein or peptide, these residues were likely to spread into the grooves of the nano-groove, nano-concave, and nano-pillar HA, further strengthening the interactions. These results are helpful in better understanding the adsorption behaviors of proteins onto nano-structured HA surfaces, and provide theoretical guidance for designing novel bioceramic materials for bone regeneration and tissue engineering.
The Association between Galectin-3 and hs-CRP and the Clinical Outcome after Non-ST-Elevation Myocardial Infarction with Preexisting Atrial Fibrillation
Authors: Pavlović Milan , Apostolović Svetlana , Stokanović Dragana , Momčilović Stefan , Jevtović-Stoimenov Tatjana , Zdravković Snezana Ćirić , Martinović Sonja Šalinger , Krstić Nebojsa , Koraćević Goran , Djordjevic Danijela , Ćosić Vladan , Nikolic Valentina N.
Published: November 2017

Increased galectin-3 plasma concentration has been linked to an unfavorable outcome in patients with heart failure or atrial fibrillation (AF). There are no published data about the prognostic utility of galectin-3 and high-sensitivity C-reactive protein (hs-CRP) for long-term clinical outcome in the Non-ST elevation acute myocardial infarction (NSTEMI) patients with preexisting AF. Thirty-two patients with the first acute NSTEMI and preexisting AF and 22 patients without preexisting AF, were prospectively followed for fifteen months. Patients with AF had significantly higher galectin-3 plasma levels (p < 0.05) and hs-CRP concentration (p < 0.01), compared with patients without AF. Galectin-3 plasma concentration was not a significant covariate of the composite outcomes (p = 0.913). Patients with high hs-CRP (above 4.55 mg/L) showed 2.5 times increased risk (p < 0.05) of the composite outcome occurrence (p < 0.05). Besides, three-vessel coronary artery disease, creatinine serum level, and creatinine clearance were significant covariates (p < 0.05; p < 0.05; p < 0.01) of the composite outcome, respectively. Creatinine clearance, solely, has been shown to be an independent predictor of unfavorable prognosis after a 15-month follow-up. Galectin-3 and hs-CRP plasma levels were elevated in NSTEMI patients with AF, but with differential predictive value for an unfavorable clinical outcome. Only hs-CRP was associated with increased risk of composite outcome occurrence.
Carnosol controls the human glioblastoma stemness features through the epithelial-mesenchymal transition modulation and the induction of cancer stem cell apoptosis
Authors: Giacomelli Chiara , Daniele Simona , Natali Letizia , Iofrida Caterina , Flamini Guido , Braca Alessandra , Trincavelli M. Letizia , Martini Claudia
Published: November 2017

A high cell proliferation rate, invasiveness and resistance to chemotherapy are the main features of glioblastoma (GBM). GBM aggressiveness has been widely associated both with a minor population of cells presenting stem-like properties (cancer stem-like cells, CSCs) and with the ability of tumor cells to acquire a mesenchymal phenotype (epithelial-mesenchymal transition, EMT). Carnosol (CAR), a natural inhibitor of MDM2/p53 complex, has been attracted attention for its anti-cancer effects on several tumor types, including GBM. Herein, the effects of CAR on U87MG-derived CSC viability and stemness features were evaluated. CAR decreased the rate of CSC formation and promoted the CSC apoptotic cell death through p53 functional reactivation. Moreover, CAR was able to control the TNF-α/TGF-β-induced EMT, counteracting the effects of the cytokine on EMT master regulator genes (Slug, Snail, Twist and ZEB1) and modulating the activation of miR-200c, a key player in the EMT process. Finally, CAR was able to increase the temozolomide (TMZ) anti-proliferative effects. These findings demonstrate that CAR affected the different intracellular mechanism of the complex machinery that regulates GBM stemness. For the first time, the diterpene was highlighted as a promising lead for the development of agents able to decrease the stemness features, thus controlling GBM aggressiveness.
High-fraction brookite films from amorphous precursors
Authors: Haggerty James E. S. , Schelhas Laura T. , Kitchaev Daniil A. , Mangum John S. , Garten Lauren M. , Sun Wenhao , Stone Kevin H. , Perkins John D. , Toney Michael F. , Ceder Gerbrand , Ginley David S. , Gorman Brian P. , Tate Janet
Published: November 2017

Structure-specific synthesis processes are of key importance to the growth of polymorphic functional compounds such as TiO2, where material properties strongly depend on structure as well as chemistry. The robust growth of the brookite polymorph of TiO2, a promising photocatalyst, has been difficult in both powder and thin-film forms due to the disparity of reported synthesis techniques, their highly specific nature, and lack of mechanistic understanding. In this work, we report the growth of high-fraction (~95%) brookite thin films prepared by annealing amorphous titania precursor films deposited by pulsed laser deposition. We characterize the crystallization process, eliminating the previously suggested roles of substrate templating and Na helper ions in driving brookite formation. Instead, we link phase selection directly to film thickness, offering a novel, generalizable route to brookite growth that does not rely on the presence of extraneous elements or particular lattice-matched substrates. In addition to providing a new synthesis route to brookite thin films, our results take a step towards resolving the problem of phase selection in TiO2 growth, contributing to the further development of this promising functional material.
Deep sequencing and analyses of miRNAs, isomiRs and miRNA induced silencing complex (miRISC)-associated miRNome in primary human chondrocytes
Authors: Haseeb Abdul , Makki Mohammad Shahidul , Khan Nazir M. , Ahmad Imran , Haqqi Tariq M.
Published: November 2017

MicroRNAs, a group of small, noncoding RNAs that post-transcriptionally regulate gene expression, play important roles in chondrocyte function and in the development of osteoarthritis. We characterized the dynamic repertoire of the chondrocyte miRNome and miRISC-associated miRNome by deep sequencing analysis of primary human chondrocytes. IL-1β treatment showed a modest effect on the expression profile of miRNAs in normal and osteoarthritis (OA) chondrocytes. We found a number of miRNAs that showed a wide range of sequence modifications including nucleotide additions and deletions at 5′ and 3′ ends; and nucleotide substitutions. miR-27b-3p showed the highest expression and miR-140-3p showed the highest number of sequence variations. AGO2 RIP-Seq analysis revealed the differential recruitment of a subset of expressed miRNAs and isoforms of miRNAs (isomiRs) to the miRISC in response to IL-1β, including miR-146a-5p, miR-155-5p and miR-27b-3p. Together, these results reveal a complex repertoire of miRNAs and isomiRs in primary human chondrocytes. Here, we also show the changes in miRNA composition of the miRISC in primary human chondrocytes in response to IL-1β treatment. These findings will provide an insight to the miRNA-mediated control of gene expression in the pathogenesis of OA.
Slow waves in locally resonant metamaterials line defect waveguides
Authors: Kaina Nadège , Causier Alexandre , Bourlier Yoan , Fink Mathias , Berthelot Thomas , Lerosey Geoffroy
Published: November 2017

Many efforts have been devoted to wave slowing, as it is essential, for instance, in analog signal computing and is one prerequisite for increased wave/matter interactions. Despite the interest of many communities, researches have mostly been conducted in optics, where wavelength-scaled structured composite media are promising candidates for compact slow light components. Yet their structural scale prevents them from being transposed to lower frequencies. Here, we propose to overcome this limitation using the deep sub-wavelength scale of locally resonant metamaterials. We experimentally show, in the microwave regime, that introducing coupled resonant defects in such metamaterials creates sub-wavelength waveguides in which wave propagation exhibit reduced group velocities. We qualitatively explain the mechanism underlying this slow wave propagation and demonstrate how it can be used to tune the velocity, achieving group indices as high as 227. We conclude by highlighting the three beneficial consequences of our line defect slow wave waveguides: (1) the sub-wavelength scale making it a compact platform for low frequencies (2) the large group indices that together with the extreme field confinement enables efficient wave/matter interactions and (3) the fact that, contrarily to other approaches, slow wave propagation does not occur at the expense of drastic bandwidth reductions.
Enhanced physicochemical properties of polydimethylsiloxane based microfluidic devices and thin films by incorporating synthetic micro-diamond
Authors: Waheed Sidra , Cabot Joan M. , Macdonald Niall P. , Kalsoom Umme , Farajikhah Syamak , Innis Peter C. , Nesterenko Pavel N. , Lewis Trevor W. , Breadmore Michael C. , Paull Brett
Published: November 2017

Synthetic micro-diamond-polydimethylsiloxane (PDMS) composite microfluidic chips and thin films were produced using indirect 3D printing and spin coating fabrication techniques. Microfluidic chips containing up to 60 wt% micro-diamond were successfully cast and bonded. Physicochemical properties, including the dispersion pattern, hydrophobicity, chemical structure, elasticity and thermal characteristics of both chip and films were investigated. Scanning electron microscopy indicated that the micro-diamond particles were embedded and interconnected within the bulk material of the cast microfluidic chip, whereas in the case of thin films their increased presence at the polymer surface resulted in a reduced hydrophobicity of the composite. The elastic modulus increased from 1.28 for a PDMS control, to 4.42 MPa for the 60 wt% composite, along with a three-fold increase in thermal conductivity, from 0.15 to 0.45 W m−1 K−1. Within the fluidic chips, micro-diamond incorporation enhanced heat dissipation by efficient transfer of heat from within the channels to the surrounding substrate. At a flow rate of 1000 μL/min, the gradient achieved for the 60 wt% composite chip equalled a 9.8 °C drop across a 3 cm long channel, more than twice that observed with the PDMS control chip.