bluuebunny/crossref_metadata_2025_split huggingface dataset:
On the Development of a Method for Updating an Empirical Climatological Ionospheric Model by Means of Assimilated vTEC Measurements From a GNSS Receiver Network
Authors: Pignalberi A. , Habarulema J.B. , Pezzopane M. , Rizzi R. 
Published: June 2019

AbstractIn this paper, a procedure for updating the International Reference Ionosphere (IRI) model by means of assimilated vertical total electron content (vTEC) measurements from a Global Navigational Satellite Systems (GNSS) receiver network is presented. This procedure stands as an additional implementation of the IRI UPdate (IRI UP) method, which is based on the assimilation of ionosonde derived F2 layer ionospheric characteristics. According to this, a mathematical procedure for obtaining foF2 and M(3000)F2 values from vTEC measurements is here proposed. Mathematical relationships between F2 layer characteristics and vTEC values have been derived using South African colocated ionosonde and GNSS stations. The same procedure can, however, be applied successfully in each region where such data are available. The goodness of the proposed IRI UP method, based on assimilated vTEC values, has been tested for several quiet and disturbed days in 2017 and 2018. IRI UP exhibits better performances than IRI for foF2, for most of the analyzed cases. Slight improvements are achieved in modeling hmF2 only for very disturbed periods in 2017. Due to the very good coverage of the terrestrial surface that GNSS receivers have achieved in recent years, we suggest that the method proposed here can be a good implementation of the IRI model for Space Weather nowcasting purposes, at least for foF2.
Coulomb pre-stress and fault bends are ignored yet vital factors for earthquake triggering and hazard
Authors: Mildon Z. K. , Roberts G. P. , Faure Walker J. P. , Toda S. 
Published: June 2019

AbstractSuccessive locations of individual large earthquakes (Mw > 5.5) over years to centuries can be difficult to explain with simple Coulomb stress transfer (CST) because it is common for seismicity to circumvent nearest-neighbour along-strike faults where coseismic CST is greatest. We demonstrate that Coulomb pre-stress (the cumulative CST from multiple earthquakes and interseismic loading on non-planar faults) may explain this, evidenced by study of a 667-year historical record of earthquakes in central Italy. Heterogeneity in Coulomb pre-stresses across the fault system is >±50 bars, whereas coseismic CST is <±2 bars, so the latter will rarely overwhelm the former, explaining why historical earthquakes rarely rupture nearest neighbor faults. However, earthquakes do tend to occur where the cumulative coseismic and interseismic CST is positive, although there are notable examples where earthquake propagate across negatively stressed portions of faults. Hence Coulomb pre-stress calculated for non-planar faults is an ignored yet vital factor for earthquake triggering.
IL-33-mediated mast cell activation promotes gastric cancer through macrophage mobilization
Authors: Eissmann Moritz F. , Dijkstra Christine , Jarnicki Andrew , Phesse Toby , Brunnberg Jamina , Poh Ashleigh R. , Etemadi Nima , Tsantikos Evelyn , Thiem Stefan , Huntington Nicholas D. , Hibbs Margaret L. , Boussioutas Alex , Grimbaldeston Michele A. , Buchert Michael , O’Donoghue Robert J. J. , Masson Frederick , Ernst Matthias 
Published: June 2019

AbstractThe contribution of mast cells in the microenvironment of solid malignancies remains controversial. Here we functionally assess the impact of tumor-adjacent, submucosal mast cell accumulation in murine and human intestinal-type gastric cancer. We find that genetic ablation or therapeutic inactivation of mast cells suppresses accumulation of tumor-associated macrophages, reduces tumor cell proliferation and angiogenesis, and diminishes tumor burden. Mast cells are activated by interleukin (IL)-33, an alarmin produced by the tumor epithelium in response to the inflammatory cytokine IL-11, which is required for the growth of gastric cancers in mice. Accordingly, ablation of the cognate IL-33 receptor St2 limits tumor growth, and reduces mast cell-dependent production and release of the macrophage-attracting factors Csf2, Ccl3, and Il6. Conversely, genetic or therapeutic macrophage depletion reduces tumor burden without affecting mast cell abundance. Therefore, tumor-derived IL-33 sustains a mast cell and macrophage-dependent signaling cascade that is amenable for the treatment of gastric cancer.
Reduced subcutaneous adipogenesis in human hypertrophic obesity is linked to senescent precursor cells
Authors: Gustafson Birgit , Nerstedt Annika , Smith Ulf 
Published: June 2019

AbstractInappropriate expansion of the adipose cells in the subcutaneous adipose tissue (SAT) is a characteristic of hypertrophic obesity and of individuals with genetic predisposition for T2D (first-degree relatives; FDR). It is associated with insulin resistance, a dysfunctional, adipose tissue and reduced adipogenesis. We examined the regulation of adipogenesis in human SAT precursor cells and found ZNF521 to be a critical regulator of early adipogenic commitment and precursor cells leaving the cell cycle. However, neither altered upstream signalling nor lack of SAT progenitor cells could explain the reduced adipogenesis in hypertrophic obesity. Instead, we show that progenitor cells undergoing poor differentiation are characterized by senescence, inability to suppress p53/P16INK4 and secretion of factors reducing adipogenesis in non-senescent cells. We found aging, FDR and established T2D to be associated with increased progenitor cell senescence, reduced adipogenesis and hypertrophic expansion of the SAT adipose cells.
Thermoresponsive nanoemulsion-based gel synthesized through a low-energy process
Authors: Hashemnejad Seyed Meysam , Badruddoza Abu Zayed Md , Zarket Brady , Ricardo Castaneda Carlos , Doyle Patrick S. 
Published: June 2019

AbstractThermoresponsive nanoemulsions find utility in applications ranging from food to pharmaceuticals to consumer products. Prior systems have found limited translation to applications due to cytotoxicity of the compositions and/or difficulties in scaling-up the process. Here, we report a route to thermally gel an oil-in-water nanoemulsion using a small amount of FDA-approved amphiphilic triblock Pluronic copolymers which act as gelling agents. At ambient temperature the suspension displays liquid-like behavior, and quickly becomes an elastic gel at elevated temperatures. We propose a gelation mechanism triggered by synergistic action of thermally-induced adsorption of Pluronic copolymers onto the droplet interface and an increased micelle concentration in the aqueous solution. We demonstrate that the system’s properties can be tuned via many factors and report their rheological properties. The nanoemulsions are prepared using a low-energy process which offers an efficient route to scale-up. The nanoemulsion formulations are well-suited for use in cosmetics and pharmaceutical applications.
Molecular phenotyping of the surfaceome of migratory chondroprogenitors and mesenchymal stem cells using biotinylation, glycocapture and quantitative LC-MS/MS proteomic analysis
Authors: Matta Csaba , Boocock David J. , Fellows Christopher R. , Miosge Nicolai , Dixon James E. , Liddell Susan , Smith Julia , Mobasheri Ali 
Published: June 2019

AbstractThe complement of cell surface proteins, collectively referred to as the surfaceome, is a useful indicator of normal differentiation processes, and the development of pathologies such as osteoarthritis (OA). We employed biochemical and proteomic tools to explore the surfaceome and to define biomarkers in chondrogenic progenitor cells (CPC) derived from human OA knee articular cartilage. These cells have great therapeutic potential, but their unexplored biology limits their clinical application. We performed biotinylation combined with glycocapture and high throughput shotgun proteomics to define the surface proteome of human bone marrow mesenchymal stem cells (MSCs) and human CPCs. We prepared cell surface protein-enriched fractions from MSCs and CPCs, and then a proteomic approach was used to compare and evaluate protein changes between undifferentiated MSCs and CPCs. 1256 proteins were identified in the study, of which 791 (63%) were plasma membrane, cell surface or extracellular matrix proteins. Proteins constituting the surfaceome were annotated and categorized. Our results provide, for the first time, a repository of quantitative proteomic data on the surfaceome of two closely related cell types relevant to cartilage biology and OA. These results may provide novel insights into the transformation of the surfaceome during chondrogenic differentiation and phenotypic changes during OA development.
Analytical level set fabrication constraints for inverse design
Authors: Vercruysse Dries , Sapra Neil V. , Su Logan , Trivedi Rahul , Vučković Jelena 
Published: June 2019

AbstractInverse design methods produce nanophotonic devices with arbitrary geometries that show high efficiencies as well as novel functionalities. Ensuring fabricability during optimization of these unrestricted device geometries is a major challenge for these design methods. In this work, we construct a fabrication constraint penalty function for level set geometry representations of these devices. This analytical penalty function limits both the gap size and boundary curvature of a device. We incorporate this penalty in a fully automated optical design flow using a quasi-Newton optimization method. The performance of our design method is evaluated by designing a series of waveguide demultiplexers (WDM) and mode converters with various footprints and minimum feature sizes. Finally, we design and experimentally characterize three WDMs with a 80 nm, 120 nm and 160 nm feature size.
Direct measurement and analytical description of the mode alignment in inversely tapered silicon nano-resonators
Authors: Schmitt Sebastian W. , Schwarzburg Klaus , Dubourdieu Catherine 
Published: June 2019

AbstractInversely tapered silicon photonic resonators on silicon substrates were shown to host multiple high–Q whispering gallery modes and constitute versatile building blocks for CMOS compatible solid state lighting, optical sensing and modulator devices. So far, numerical analyses by the finite difference time domain method have been used to predict the height distribution of whispering gallery modes in such resonators. In this study, we provide an experimental evidence of this mode distribution along the resonator height by selectively exciting whispering gallery modes using cathodoluminescence spectroscopy. Further we derive analytical functions that permit to relate the height distribution of modes with a defined polarization, symmetry and effective refractive index to the geometrical shape of the inversely tapered resonators.
Chromatin Compaction by Small RNAs and the Nuclear RNAi Machinery in C. elegans
Authors: Fields Brandon D. , Kennedy Scott 
Published: June 2019

AbstractDNA is organized and compacted into higher-order structures in order to fit within nuclei and to facilitate gene regulation. Mechanisms by which higher order chromatin structures are established and maintained are poorly understood. In C. elegans, nuclear-localized small RNAs engage the nuclear RNAi machinery to regulate gene expression and direct the post-translational modification of histone proteins. Here we confirm a recent report suggesting that nuclear small RNAs initiate or maintain chromatin compaction states in C. elegans germ cells. Additionally, we show that experimentally provided small RNAs are sufficient to direct chromatin compaction and that this compaction requires the small RNA-binding Argonaute NRDE-3, the pre-mRNA associated factor NRDE-2, and the HP1-like protein HPL-2. Our results show that small RNAs, acting via the nuclear RNAi machinery and an HP1-like protein, are capable of driving chromatin compaction in C. elegans.
Conversion of human and mouse fibroblasts into lung-like epithelial cells
Authors: Wong Amy P. , Shojaie Sharareh , Liang Qin , Xia Sunny , Di Paola Michelle , Ahmadi Saumel , Bilodeau Claudia , Garner Jodi , Post Martin , Duchesneau Pascal , Waddell Thomas K. , Bear Christine E. , Nagy Andras , Rossant Janet 
Published: June 2019

AbstractCell lineage conversion of fibroblasts to specialized cell types through transdifferentiation may provide a fast and alternative cell source for regenerative medicine. Here we show that transient transduction of fibroblasts with the four reprogramming factors (Oct4, Sox2, Klf4, and c-Myc) in addition to the early lung transcription factor Nkx2-1 (also known as Ttf1), followed by directed differentiation of the cells, can convert mouse embryonic and human adult dermal fibroblasts into induced lung-like epithelial cells (iLEC). These iLEC differentiate into multiple lung cell types in air liquid interface cultures, repopulate decellularized rat lung scaffolds, and form lung epithelia composed of Ciliated, Goblet, Basal, and Club cells after transplantation into immune-compromised mice. As proof-of-concept, differentiated human iLEC harboring the Cystic Fibrosis mutation dF508 demonstrated pharmacological rescue of CFTR function using the combination of lumacaftor and ivacaftor. Overall, this is a promising alternative approach for generation of patient-specific lung-like progenitors to study lung function, disease and future regeneration strategies.
Mutational mimics of allosteric effectors: a genome editing design to validate allosteric drug targets
Authors: Tang Qingling , Villar Maria T. , Artigues Antonio , Thyfault John P. , Apte Udayan , Zhu Hao , Peterson Kenneth R. , Fenton Aron W. 
Published: June 2019

AbstractDevelopment of drugs that allosterically regulate enzyme functions to treat disease is a costly venture. Amino acid susbstitutions that mimic allosteric effectors in vitro will identify therapeutic regulatory targets enhancing the likelihood of developing a disease treatment at a reasonable cost. We demonstrate the potential of this approach utilizing human liver pyruvate kinase (hLPYK) as a model. Inhibition of hLPYK was the first desired outcome of this study. We identified individual point mutations that: 1) mimicked allosteric inhibition by alanine, 2) mimicked inhibition by protein phosphorylation, and 3) prevented binding of fructose-1,6-bisphosphate (Fru-1,6-BP). Our second desired outcome was activation of hLPYK. We identified individual point mutations that: 1) prevented hLPYK from binding alanine, the allosteric inhibitor, 2) prevented inhibitory protein phosphorylation, or 3) mimicked allosteric activation by Fru-1,6-BP. Combining the three activating point mutations produced a constitutively activated enzyme that was unresponsive to regulators. Expression of a mutant hLPYK transgene containing these three mutations in a mouse model was not lethal. Thus, mutational mimics of allosteric effectors will be useful to confirm whether allosteric activation of hLPYK will control glycolytic flux in the diabetic liver to reduce hepatic glucose production and, in turn, reduce or prevent hyperglycemia.
Multidimensional diffusion MRI with spectrally modulated gradients reveals unprecedented microstructural detail
Authors: Lundell H. , Nilsson M. , Dyrby T. B. , Parker G. J. M. , Cristinacce P. L. Hubbard , Zhou F.-L. , Topgaard D. , Lasič S. 
Published: June 2019

AbstractCharacterization of porous media is essential in a wide range of biomedical and industrial applications. Microstructural features can be probed non-invasively by diffusion magnetic resonance imaging (dMRI). However, diffusion encoding in conventional dMRI may yield similar signatures for very different microstructures, which represents a significant limitation for disentangling individual microstructural features in heterogeneous materials. To solve this problem, we propose an augmented multidimensional diffusion encoding (MDE) framework, which unlocks a novel encoding dimension to assess time-dependent diffusion specific to structures with different microscopic anisotropies. Our approach relies on spectral analysis of complex but experimentally efficient MDE waveforms. Two independent contrasts to differentiate features such as cell shape and size can be generated directly by signal subtraction from only three types of measurements. Analytical calculations and simulations support our experimental observations. Proof-of-concept experiments were applied on samples with known and distinctly different microstructures. We further demonstrate substantially different contrasts in different tissue types of a post mortem brain. Our simultaneous assessment of restriction size and shape may be instrumental in studies of a wide range of porous materials, enable new insights into the microstructure of biological tissues or be of great value in diagnostics.
Involvement of Hsp90 and cyclophilins in intoxication by AIP56, a metalloprotease toxin from Photobacterium damselae subsp. piscicida
Authors: Rodrigues Inês S. , Pereira Liliana M. G. , Lisboa Johnny , Pereira Cassilda , Oliveira Pedro , dos Santos Nuno M. S. , do Vale Ana 
Published: June 2019

AbstractAIP56 (apoptosis inducing protein of 56 kDa) is a key virulence factor secreted by virulent strains of Photobacterium damselae subsp. piscicida (Phdp), a Gram-negative bacterium that causes septicemic infections in several warm water marine fish species. AIP56 is systemically disseminated during infection and induces massive apoptosis of host macrophages and neutrophils, playing a decisive role in the disease outcome. AIP56 is a single-chain AB-type toxin, being composed by a metalloprotease A domain located at the N-terminal region connected to a C-terminal B domain, required for internalization of the toxin into susceptible cells. After binding to a still unidentified surface receptor, AIP56 is internalised through clathrin-mediated endocytosis, reaches early endosomes and translocates into the cytosol through a mechanism requiring endosomal acidification and involving low pH-induced unfolding of the toxin. At the cytosol, the catalytic domain of AIP56 cleaves NF-κB p65, leading to the apoptotic death of the intoxicated cells. It has been reported that host cytosolic factors, including host cell chaperones such as heat shock protein 90 (Hsp90) and peptidyl-prolyl cis/trans isomerases (PPIases), namely cyclophilin A/D (Cyp) and FK506-binding proteins (FKBP) are involved in the uptake of several bacterial AB toxins with ADP-ribosylating activity, but are dispensable for the uptake of other AB toxins with different enzymatic activities, such as Bacillus anthracis lethal toxin (a metalloprotease) or the large glycosylating toxins A and B of Clostridium difficile. Based on these findings, it has been proposed that the requirement for Hsp90/PPIases is a common and specific characteristic of ADP-ribosylating toxins. In the present work, we demonstrate that Hsp90 and the PPIases cyclophilin A/D are required for efficient intoxication by the metalloprotease toxin AIP56. We further show that those host cell factors interact with AIP56 in vitro and that the interactions increase when AIP56 is unfolded. The interaction with Hsp90 was also demonstrated in intact cells, at 30 min post-treatment with AIP56, suggesting that it occurs during or shortly after translocation of the toxin from endosomes into the cytosol. Based on these findings, we propose that the participation of Hsp90 and Cyp in bacterial toxin entry may be more disseminated than initially expected, and may include toxins with different catalytic activities.
NTHL1 biallelic mutations seldom cause colorectal cancer, serrated polyposis or a multi-tumor phenotype, in absence of colorectal adenomas
Authors: Belhadj Sami , Quintana Isabel , Mur Pilar , Munoz-Torres Pau M. , Alonso M. Henar , Navarro Matilde , Terradas Mariona , Piñol Virginia , Brunet Joan , Moreno Victor , Lázaro Conxi , Capellá Gabriel , Valle Laura 
Published: June 2019

AbstractThe cancer-predisposing syndrome caused by biallelic mutations in NTHL1 may not be a solely colorectal cancer (CRC) and polyposis syndrome but rather a multi-tumor recessive disease. The presence of ≤10 adenomas in several mutation carriers suggests a possible causal role of NTHL1 in hereditary or early-onset nonpolyposis CRC. The involvement of NTHL1 in serrated/hyperplastic polyposis remains unexplored. The aim of our study is to elucidate the role of NTHL1 in the predisposition to personal or familial history of multiple tumor types, familial/early-onset nonpolyposis CRC, and serrated polyposis. NTHL1 mutational screening was performed in 312 cancer patients with personal or family history of multiple tumor types, 488 with hereditary nonpolyposis CRC, and 96 with serrated/hyperplastic polyposis. While no biallelic mutation carriers were identified in patients with personal and/or family history of multiple tumor types or with serrated polyposis, one was identified among the 488 nonpolyposis CRC patients. The carrier of c.268C>T (p.Q90*) and 550-1G>A was diagnosed with CRC and meningioma at ages 37 and 45 respectively, being reclassified as attenuated adenomatous polyposis after the cumulative detection of 26 adenomas. Our findings suggest that biallelic mutations in NTHL1 rarely cause CRC, a personal/familial multi-tumor history, or serrated polyposis, in absence of adenomas.
Immunization with merozoite surface protein 2 fused to a Plasmodium-specific carrier protein elicits strain-specific and strain-transcending, opsonizing antibody
Authors: Eacret Jacqueline S. , Gonzales Donna M. , Franks Raymond G. , Burns James M. 
Published: June 2019

AbstractVaccine trials and cohort studies in Plasmodium falciparum endemic areas indicate that naturally-acquired and vaccine-induced antibodies to merozoite surface protein 2 (MSP2) are associated with resistance to malaria. These data indicate that PfMSP2 has significant potential as a component of a multi-antigen malaria vaccine. To overcome challenges encountered with subunit malaria vaccines, we established that the use of highly immunogenic rPfMSP8 as a carrier protein for leading vaccine candidates rPfMSP119 and rPfs25 facilitated antigen production, minimized antigenic competition and enhanced induction of functional antibodies. We applied this strategy to optimize a rPfMSP2 (3D7)-based subunit vaccine by producing unfused rPfMSP2 or chimeric rPfMSP2/8 in Escherichia coli. rPfMSP2 formed fibrils, which induced splenocyte proliferation in an antigen receptor-independent, TLR2-dependent manner. However, fusion to rPfMSP8 prevented rPfMSP2 amyloid-like fibril formation. Immunization of rabbits elicited high-titer anti-PfMSP2 antibodies that recognized rPfMSP2 of the 3D7 and FC27 alleles, as well as native PfMSP2. Competition assays revealed a difference in the specificity of antibodies induced by the two rPfMSP2-based vaccines, with evidence of epitope masking by rPfMSP2-associated fibrils. Rabbit anti-PfMSP2/8 was superior to rPfMSP2-elicited antibody at opsonizing P. falciparum merozoites for phagocytosis. These data establish rPfMSP8 as an effective carrier for a PfMSP2-based subunit malaria vaccine.