bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiplex imaging relates quantal glutamate release to presynaptic Ca2+ homeostasis at multiple synapses in situ
Authors: Jensen Thomas P. , Zheng Kaiyu , Cole Nicholas , Marvin Jonathan S. , Looger Loren L. , Rusakov Dmitri A. 
Published: March 2019

AbstractInformation processing by brain circuits depends on Ca2+-dependent, stochastic release of the excitatory neurotransmitter glutamate. Whilst optical glutamate sensors have enabled detection of synaptic discharges, understanding presynaptic machinery requires simultaneous readout of glutamate release and nanomolar presynaptic Ca2+ in situ. Here, we find that the fluorescence lifetime of the red-shifted Ca2+ indicator Cal-590 is Ca2+-sensitive in the nanomolar range, and employ it in combination with green glutamate sensors to relate quantal neurotransmission to presynaptic Ca2+ kinetics. Multiplexed imaging of individual and multiple synapses in identified axonal circuits reveals that glutamate release efficacy, but not its short-term plasticity, varies with time-dependent fluctuations in presynaptic resting Ca2+ or spike-evoked Ca2+ entry. Within individual presynaptic boutons, we find no nanoscopic co-localisation of evoked presynaptic Ca2+ entry with the prevalent glutamate release site, suggesting loose coupling between the two. The approach enables a better understanding of release machinery at central synapses.
Ligand design strategies to increase stability of gadolinium-based magnetic resonance imaging contrast agents
Authors: Clough Thomas J. , Jiang Lijun , Wong Ka-Leung , Long Nicholas J. 
Published: March 2019

AbstractGadolinium(III) complexes have been widely utilised as magnetic resonance imaging (MRI) contrast agents for decades. In recent years however, concerns have developed about their toxicity, believed to derive from demetallation of the complexes in vivo, and the relatively large quantities of compound required for a successful scan. Recent efforts have sought to enhance the relaxivity of trivalent gadolinium complexes without sacrificing their stability. This review aims to examine the strategic design of ligands synthesised for this purpose, provide an overview of recent successes in gadolinium-based contrast agent development and assess the requirements for clinical translation.
The architecture of functional lateralisation and its relationship to callosal connectivity in the human brain
Authors: Karolis Vyacheslav R. , Corbetta Maurizio , Thiebaut de Schotten Michel 
Published: March 2019

AbstractFunctional lateralisation is a fundamental principle of the human brain. However, a comprehensive taxonomy of functional lateralisation and its organisation in the brain is missing. Here, we report the first complete map of functional hemispheric asymmetries in the human brain, reveal its low dimensional structure, and its relationship with structural inter-hemispheric connectivity. Our results suggest that the lateralisation of brain functions is distributed along four functional axes: symbolic communication, perception/action, emotion, and decision-making. The similarity between this finding and recent work on neurological symptoms give rise to new hypotheses on the mechanisms that support brain recovery after a brain lesion. We also report that cortical regions showing asymmetries in task-evoked activity have reduced connections with the opposite hemisphere. This latter result suggests that during evolution, brain size expansion led to functional lateralisation to avoid excessive conduction delays between the hemispheres.
Semi-solid prodrug nanoparticles for long-acting delivery of water-soluble antiretroviral drugs within combination HIV therapies
Authors: Hobson James J. , Al-khouja Amer , Curley Paul , Meyers David , Flexner Charles , Siccardi Marco , Owen Andrew , Meyers Caren Freel , Rannard Steve P. 
Published: March 2019

AbstractThe increasing global prevalence of human immunodeficiency virus (HIV) is estimated at 36.7 million people currently infected. Lifelong antiretroviral (ARV) drug combination dosing allows management as a chronic condition by suppressing circulating viral load to allow for a near-normal life; however, the daily burden of oral administration may lead to non-adherence and drug resistance development. Long-acting (LA) depot injections of nanomilled poorly water-soluble ARVs have shown highly promising clinical results with drug exposure largely maintained over months after a single injection. ARV oral combinations rely on water-soluble backbone drugs which are not compatible with nanomilling. Here, we evaluate a unique prodrug/nanoparticle formation strategy to facilitate semi-solid prodrug nanoparticles (SSPNs) of the highly water-soluble nucleoside reverse transcriptase inhibitor (NRTI) emtricitabine (FTC), and injectable aqueous nanodispersions; in vitro to in vivo extrapolation (IVIVE) modelling predicts sustained prodrug release, with activation in relevant biological environments, representing a first step towards complete injectable LA regimens containing NRTIs.
Coordination of capsule assembly and cell wall biosynthesis in Staphylococcus aureus
Authors: Rausch Marvin , Deisinger Julia P. , Ulm Hannah , Müller Anna , Li Wenjin , Hardt Patrick , Wang Xiaogang , Li Xue , Sylvester Marc , Engeser Marianne , Vollmer Waldemar , Müller Christa E. , Sahl Hans Georg , Lee Jean Claire , Schneider Tanja 
Published: March 2019

AbstractThe Gram-positive cell wall consists of peptidoglycan functionalized with anionic glycopolymers, such as wall teichoic acid and capsular polysaccharide (CP). How the different cell wall polymers are assembled in a coordinated fashion is not fully understood. Here, we reconstitute Staphylococcus aureus CP biosynthesis and elucidate its interplay with the cell wall biosynthetic machinery. We show that the CapAB tyrosine kinase complex controls multiple enzymatic checkpoints through reversible phosphorylation to modulate the consumption of essential precursors that are also used in peptidoglycan biosynthesis. In addition, the CapA1 activator protein interacts with and cleaves lipid-linked CP precursors, releasing the essential lipid carrier undecaprenyl-phosphate. We further provide biochemical evidence that the subsequent attachment of CP is achieved by LcpC, a member of the LytR-CpsA-Psr protein family, using the peptidoglycan precursor native lipid II as acceptor substrate. The Ser/Thr kinase PknB, which can sense cellular lipid II levels, negatively controls CP synthesis. Our work sheds light on the integration of CP biosynthesis into the multi-component Gram-positive cell wall.
Wnt1 silences chemokine genes in dendritic cells and induces adaptive immune resistance in lung adenocarcinoma
Authors: Kerdidani Dimitra , Chouvardas Panagiotis , Arjo Ares Rocanin , Giopanou Ioanna , Ntaliarda Giannoula , Guo Yu Amanda , Tsikitis Mary , Kazamias Georgios , Potaris Konstantinos , Stathopoulos Georgios T. , Zakynthinos Spyros , Kalomenidis Ioannis , Soumelis Vassili , Kollias George , Tsoumakidou Maria 
Published: March 2019

AbstractLung adenocarcinoma (LUAD)-derived Wnts increase cancer cell proliferative/stemness potential, but whether they impact the immune microenvironment is unknown. Here we show that LUAD cells use paracrine Wnt1 signaling to induce immune resistance. In TCGA, Wnt1 correlates strongly with tolerogenic genes. In another LUAD cohort, Wnt1 inversely associates with T cell abundance. Altering Wnt1 expression profoundly affects growth of murine lung adenocarcinomas and this is dependent on conventional dendritic cells (cDCs) and T cells. Mechanistically, Wnt1 leads to transcriptional silencing of CC/CXC chemokines in cDCs, T cell exclusion and cross-tolerance. Wnt-target genes are up-regulated in human intratumoral cDCs and decrease upon silencing Wnt1, accompanied by enhanced T cell cytotoxicity. siWnt1-nanoparticles given as single therapy or part of combinatorial immunotherapies act at both arms of the cancer-immune ecosystem to halt tumor growth. Collectively, our studies show that Wnt1 induces immunologically cold tumors through cDCs and highlight its immunotherapeutic targeting.
Partially coherent radar unties range resolution from bandwidth limitations
Authors: Komissarov Rony , Kozlov Vitali , Filonov Dmitry , Ginzburg Pavel 
Published: March 2019

AbstractIt is widely believed that range resolution, the ability to distinguish between two closely situated targets, depends inversely on the bandwidth of the transmitted radar signal. Here we demonstrate a different type of ranging system, which possesses superior range resolution that is almost completely free of bandwidth limitations. By sweeping over the coherence length of the transmitted signal, the partially coherent radar experimentally demonstrates an improvement of over an order of magnitude in resolving targets, compared to standard coherent radars with the same bandwidth. A theoretical framework is developed to show that the resolution could be further improved without a bound, revealing a tradeoff between bandwidth and sweep time. This concept offers solutions to problems which require high range resolution and accuracy but available bandwidth is limited, as is the case for the autonomous car industry, optical imaging, and astronomy to name just few.
Abnormal mGluR-mediated synaptic plasticity and autism-like behaviours in Gprasp2 mutant mice
Authors: Edfawy Mohamed , Guedes Joana R. , Pereira Marta I. , Laranjo Mariana , Carvalho Mário J. , Gao Xian , Ferreira Pedro A. , Caldeira Gladys , Franco Lara O. , Wang Dongqing , Cardoso Ana Luisa , Feng Guoping , Carvalho Ana Luisa , Peça João 
Published: March 2019

AbstractAutism spectrum disorder (ASD) is characterized by dysfunction in social interactions, stereotypical behaviours and high co-morbidity with intellectual disability. A variety of syndromic and non-syndromic neurodevelopmental disorders have been connected to alterations in metabotropic glutamate receptor (mGluR) signalling. These receptors contribute to synaptic plasticity, spine maturation and circuit development. Here, we investigate the physiological role of Gprasp2, a gene linked to neurodevelopmental disabilities and involved in the postendocytic sorting of G-protein-coupled receptors. We show that Gprasp2 deletion leads to ASD-like behaviour in mice and alterations in synaptic communication. Manipulating the levels of Gprasp2 bidirectionally modulates the surface availability of mGluR5 and produces alterations in dendritic complexity, spine density and synaptic maturation. Loss of Gprasp2 leads to enhanced hippocampal long-term depression, consistent with facilitated mGluR-dependent activation. These findings demonstrate a role for Gprasp2 in glutamatergic synapses and suggest a possible mechanism by which this gene is linked to neurodevelopmental diseases.
Shp-2 is critical for ERK and metabolic engagement downstream of IL-15 receptor in NK cells
Authors: Niogret Charlène , Miah S. M. Shahjahan , Rota Giorgia , Fonta Nicolas P. , Wang Haiping , Held Werner , Birchmeier Walter , Sexl Veronica , Yang Wentian , Vivier Eric , Ho Ping-Chih , Brossay Laurent , Guarda Greta 
Published: March 2019

AbstractThe phosphatase Shp-2 was implicated in NK cell development and functions due to its interaction with NK inhibitory receptors, but its exact role in NK cells is still unclear. Here we show, using mice conditionally deficient for Shp-2 in the NK lineage, that NK cell development and responsiveness are largely unaffected. Instead, we find that Shp-2 serves mainly to enforce NK cell responses to activation by IL-15 and IL-2. Shp-2-deficient NK cells have reduced proliferation and survival when treated with high dose IL-15 or IL-2. Mechanistically, Shp-2 deficiency hampers acute IL-15 stimulation-induced raise in glycolytic and respiration rates, and causes a dramatic defect in ERK activation. Moreover, inhibition of the ERK and mTOR cascades largely phenocopies the defect observed in the absence of Shp-2. Together, our data reveal a critical function of Shp-2 as a molecular nexus bridging acute IL-15 signaling with downstream metabolic burst and NK cell expansion.
Charge density wave memory in a cuprate superconductor
Authors: Chen X. M. , Mazzoli C. , Cao Y. , Thampy V. , Barbour A. M. , Hu W. , Lu M. , Assefa T. A. , Miao H. , Fabbris G. , Gu G. D. , Tranquada J. M. , Dean M. P. M. , Wilkins S. B. , Robinson I. K. 
Published: March 2019

AbstractAlthough CDW correlations are a ubiquitous feature of the superconducting cuprates, their disparate properties suggest a crucial role for pinning the CDW to the lattice. Here, we report coherent resonant X-ray speckle correlation analysis, which directly determines the reproducibility of CDW domain patterns in La1.875Ba0.125CuO4 (LBCO 1/8) with thermal cycling. While CDW order is only observed below 54 K, where a structural phase transition creates inequivalent Cu-O bonds, we discover remarkably reproducible CDW domain memory upon repeated cycling to far higher temperatures. That memory is only lost on cycling to 240(3) K, which recovers the four-fold symmetry of the CuO2 planes. We infer that the structural features that develop below 240 K determine the CDW pinning landscape below 54 K. This opens a view into the complex coupling between charge and lattice degrees of freedom in superconducting cuprates.
Mouse models of Loa loa
Authors: Pionnier Nicolas P. , Sjoberg Hanna , Chunda Valerine C. , Fombad Fanny F. , Chounna Patrick W. , Njouendou Abdel J. , Metuge Haelly M. , Ndzeshang Bertrand L. , Gandjui Narcisse V. , Akumtoh Desmond N. , Tayong Dizzle B. , Taylor Mark J. , Wanji Samuel , Turner Joseph D. 
Published: March 2019

AbstractElimination of the helminth disease, river blindness, remains challenging due to ivermectin treatment-associated adverse reactions in loiasis co-infected patients. Here, we address a deficit in preclinical research tools for filarial translational research by developing Loa loa mouse infection models. We demonstrate that adult Loa loa worms in subcutaneous tissues, circulating microfilariae (mf) and presence of filarial biomarkers in sera occur following experimental infections of lymphopenic mice deficient in interleukin (IL)-2/7 gamma-chain signaling. A microfilaraemic infection model is also achievable, utilizing immune-competent or -deficient mice infused with purified Loa mf. Ivermectin but not benzimidazole treatments induce rapid decline (>90%) in parasitaemias in microfilaraemic mice. We identify up-regulation of inflammatory markers associated with allergic type-2 immune responses and eosinophilia post-ivermectin treatment. Thus, we provide validation of murine research models to identify loiasis biomarkers, to counter-screen candidate river blindness cures and to interrogate the inflammatory etiology of loiasis ivermectin-associated adverse reactions.
A gut microbiome signature for cirrhosis due to nonalcoholic fatty liver disease
Authors: Caussy Cyrielle , Tripathi Anupriya , Humphrey Greg , Bassirian Shirin , Singh Seema , Faulkner Claire , Bettencourt Ricki , Rizo Emily , Richards Lisa , Xu Zhenjiang Z. , Downes Michael R. , Evans Ronald M. , Brenner David A. , Sirlin Claude B. , Knight Rob , Loomba Rohit 
Published: March 2019

AbstractThe presence of cirrhosis in nonalcoholic-fatty-liver-disease (NAFLD) is the most important predictor of liver-related mortality. Limited data exist concerning the diagnostic accuracy of gut-microbiome-derived signatures for detecting NAFLD-cirrhosis. Here we report 16S gut-microbiome compositions of 203 uniquely well-characterized participants from a prospective twin and family cohort, including 98 probands encompassing the entire spectrum of NAFLD and 105 of their first-degree relatives, assessed by advanced magnetic-resonance-imaging. We show strong familial correlation of gut-microbiome profiles, driven by shared housing. We report a panel of 30 features, including 27 bacterial features with discriminatory ability to detect NAFLD-cirrhosis using a Random Forest classifier model. In a derivation cohort of probands, the model has a robust diagnostic accuracy (AUROC of 0.92) for detecting NAFLD-cirrhosis, confirmed in a validation cohort of relatives of proband with NAFLD-cirrhosis (AUROC of 0.87). This study provides evidence for a fecal-microbiome-derived signature to detect NAFLD-cirrhosis.
Integrated charge excitation triboelectric nanogenerator
Authors: Liu Wenlin , Wang Zhao , Wang Gao , Liu Guanlin , Chen Jie , Pu Xianjie , Xi Yi , Wang Xue , Guo Hengyu , Hu Chenguo , Wang Zhong Lin 
Published: March 2019

AbstractPerformance of triboelectric nanogenerators is limited by low and unstable charge density on tribo-layers. An external-charge pumping method was recently developed and presents a promising and efficient strategy towards high-output triboelectric nanogenerators. However, integratibility and charge accumulation efficiency of the system is rather low. Inspired by the historical development of electromagnetic generators, here, we propose and realize a self-charge excitation triboelectric nanogenerator system towards high and stable output in analogy to the principle of traditional magnetic excitation generators. By rational design of the voltage-multiplying circuits, the completed external and self-charge excitation modes with stable and tailorable output over 1.25 mC m−2 in contact-separation mode have been realized in ambient condition. The realization of the charge excitation system in this work may provide a promising strategy for achieving high-output triboelectric nanogenerators towards practical applications.
Excessive mechanical loading promotes osteoarthritis through the gremlin-1–NF-κB pathway
Authors: Chang Song Ho , Mori Daisuke , Kobayashi Hiroshi , Mori Yoshifumi , Nakamoto Hideki , Okada Keita , Taniguchi Yuki , Sugita Shurei , Yano Fumiko , Chung Ung-il , Kim-Kaneyama Joo-ri , Yanagita Motoko , Economides Aris , Canalis Ernesto , Chen Di , Tanaka Sakae , Saito Taku 
Published: March 2019

AbstractExposure of articular cartilage to excessive mechanical loading is deeply involved in the pathogenesis of osteoarthritis. Here, we identify gremlin-1 as a mechanical loading-inducible factor in chondrocytes, detected at high levels in middle and deep layers of cartilage after cyclic strain or hydrostatic pressure loading. Gremlin-1 activates nuclear factor-κB signalling, leading to subsequent induction of catabolic enzymes. In mice intra-articular administration of gremlin-1 antibody or chondrocyte-specific deletion ofGremlin-1decelerates osteoarthritis development, while intra-articular administration of recombinant gremlin-1 exacerbates this process. Furthermore, ras-related C3 botulinum toxin substrate 1 activation induced by mechanical loading enhances reactive oxygen species (ROS) production. Amongst ROS-activating transcription factors, RelA/p65 inducesGremlin-1transcription, which antagonizes induction of anabolic genes such asSox9,Col2a1, andAcanby bone morphogenetic proteins. Thus, gremlin-1 plays essential roles in cartilage degeneration by excessive mechanical loading.
Fabrication of arbitrary three-dimensional suspended hollow microstructures in transparent fused silica glass
Authors: Kotz Frederik , Risch Patrick , Arnold Karl , Sevim Semih , Puigmartí-Luis Josep , Quick Alexander , Thiel Michael , Hrynevich Andrei , Dalton Paul D. , Helmer Dorothea , Rapp Bastian E. 
Published: March 2019

AbstractFused silica glass is the preferred material for applications which require long-term chemical and mechanical stability as well as excellent optical properties. The manufacturing of complex hollow microstructures within transparent fused silica glass is of particular interest for, among others, the miniaturization of chemical synthesis towards more versatile, configurable and environmentally friendly flow-through chemistry as well as high-quality optical waveguides or capillaries. However, microstructuring of such complex three-dimensional structures in glass has proven evasive due to its high thermal and chemical stability as well as mechanical hardness. Here we present an approach for the generation of hollow microstructures in fused silica glass with high precision and freedom of three-dimensional designs. The process combines the concept of sacrificial template replication with a room-temperature molding process for fused silica glass. The fabricated glass chips are versatile tools for, among other, the advance of miniaturization in chemical synthesis on chip.
Electrotaxis of Glioblastoma and Medulloblastoma Spheroidal Aggregates
Authors: Lyon Johnathan G. , Carroll Sheridan L. , Mokarram Nassir , Bellamkonda Ravi V. 
Published: March 2019

AbstractTreatment of neuroepithelial cancers remains a daunting clinical challenge, particularly due to an inability to address rampant invasion deep into eloquent regions of the brain. Given the lack of access, and the dispersed nature of brain tumor cells, we explore the possibility of electric fields inducing directed tumor cell migration. In this study we investigate the properties of populations of brain cancer undergoing electrotaxis, a phenomenon whereby cells are directed to migrate under control of an electrical field. We investigate two cell lines for glioblastoma and medulloblastoma (U87mg & DAOY, respectively), plated as spheroidal aggregates in Matrigel-filled electrotaxis channels, and report opposing electrotactic responses. To further understand electrotactic migration of tumor cells, we performed RNA-sequencing for pathway discovery to identify signaling that is differentially affected by the exposure of direct-current electrical fields. Further, using selective pharmacological inhibition assays, focused on the PI3K/mTOR/AKT signaling axis, we validate whether there is a causal relationship to electrotaxis and these mechanisms of action. We find that U87 mg electrotaxis is abolished under pharmacological inhibition of PI3Kγ, mTOR, AKT and ErbB2 signaling, whereas DAOY cell electrotaxis was not attenuated by these or other pathways evaluated.
Effects of cold storage on quality of Chrysopa pallens and recovery of fecundity by insulin
Authors: Zhang Tingting , Zhang Guocai , Zhang Lisheng , Chen Hongyin , Wang Mengqing , Liu Chenxi , Mao Jianjun 
Published: March 2019

AbstractThe green lacewing, Chrysopa pallens Wesmael, is one of the most beneficial and prolific insects found in many horticultural and agricultural cropping system. Here, the effects of low temperature storage on quality of C. pallens were investigated by storing cocoons at 10 °C for different days. Results revealed, after removal from cold storage, emergence rate declined gradually as storage duration increased. After storage of 20 days, the emergence rate in cold-stored group is about 62.8% of that in unstored group. After eclosion, lifetime fecundity, preemergence period, oviposition period and longevity of adults in cold-stored group showed curves similar to emergence rate. However, preoviposition period and egg hatchability were not significantly affected by cold. After being stored for 20 days, the total fecundity of females emerging from cold-stored cocoons was about 64.5% of that of females emerging from unstored cocoons. Six days post emergence, females in cold-stored group showed apparent arrest of ovarian development and significant reductions of protease, lipase and trehalase activities when compared to unstored controls. When bovine insulin was exogenously used, the females emerging from cold-stored cocoons dramatically restored ovarian development and reproductive capacity. These results suggested that C. pallens pupae are suitable for cold storage and insulin hormone can be used as reproduction stimuli in this predatory species after cold storage.