bluuebunny/crossref_metadata_2025_split huggingface dataset:
TAZ sensitizes EGFR wild-type non-small-cell lung cancer to gefitinib by promoting amphiregulin transcription
Authors: Yuan Weiwei , Xu Wei , Li Yan , Jiang Wei , Li Yue , Huang Qiqing , Chen Bo , Wu Shuangshuang , Wang Yu , Song Weiwei , Zhao Weihong , Wu Jianqing 
Published: March 2019

AbstractComparatively less toxic and more tolerated, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are recommendable for advanced non-small-cell lung cancer (NSCLC) patients with EGFR-sensitive mutations. Some EGFR wild-type patients with specific biomarkers also show a response to the drug. TAZ is an oncogene closely associated with the therapeutic effect of EGFR-TKIs. However, this association remains to be clarified. This study aimed to clarify the mechanism through which TAZ sensitizes EGFR wild-type NSCLC to gefitinib. We used CCK-8 assays and in vivo experiments to investigate the influence of TAZ on gefitinib in EGFR wild-type NSCLC. To further validate the tumorigenic role of TAZ, we performed Human umbilical vein endothelial cell (HUVEC) tube formation and migration assays. Luciferase reporter assays, quantitative real-time PCR (qPCR), immunoblotting and Chromatin immunoprecipitation collaborated with qPCR illuminated the mechanism through which TAZ caused those phenotypes. The results showed TAZ promoted the angiogenesis of NSCLC cell lines and improved gefitinib sensitivity in EGFR wild-type NSCLC in vitro and in vivo. Luciferase reporter assays and ChIP-qPCR experiments showed TAZ upregulated AREG by promoting its transcription. EGFR signaling pathway was activated as TAZ was highly expressed. Rescue experiments were conducted to confirm the indispensable role of AREG in tumorigenesis and gefitinib sensitivity regulated by TAZ. Our study concluded that TAZ sensitized EGFR wild-type NSCLC to gefitinib through promoting amphiregulin transcription.
Discontinuous rate-stiffening in a granular composite modeled after cornstarch and water
Authors: Chen David Z. , Zheng Hu , Wang Dong , Behringer Robert P. 
Published: March 2019

AbstractCornstarch in water exhibits impact-activated solidification (IAS) and strong discontinuous shear thickening, with “shear jamming”. However, these phenomena are absent in cornstarch in ethanol. Here we show that cornstarch granules swell under ambient conditions. We postulate that this granule swelling is linked to an interparticle force scale that introduces a discontinuous rate-dependence to the generation of stable contacts between granules. We studied this force scale by coating sand with ~ 2 μm-thick polydimethysiloxane, creating a material that exhibits a similar IAS and discontinuous deformation rate-stiffening despite being a granular composite, not a suspension. This result suggests rate-dependence can be tuned by coating granular materials, introducing an interparticle force scale from rate-dependent properties present in the coating material. Our work provides insights into the unique behavior of cornstarch in water, bridges our understanding of suspensions and dry granular materials, and introduces a method to make discontinuous rate-dependent materials without suspending particles.
Characterization of an HPV33 natural variant with enhanced transcriptional activity suggests a role for C/EBPβ in the regulation of the viral early promoter
Authors: Alvarez Jennifer , Gagnon David , Coutlée François , Archambault Jacques 
Published: March 2019

AbstractThe Long Control Region (LCR) of the human papillomavirus (HPV) genome encompasses the early promoter (EP) that drives expression of the viral oncogenes in infected cells and HPV-associated cancers. Here, we report on a natural variant of HPV33 that displays higher EP activity than the prototype in transfected C33A and HeLa cervical carcinoma cells, and in the osteosarcoma U2OS cell line which supports replication of HPV episomes. This increased promoter activity was ascribed to a single nucleotide variation in the LCR, T7791C, in a putative binding site for the transcription factor C/EBPβ. T7791C abrogated binding of recombinant C/EBPβ to this site in vitro and stimulated the EP in vivo, suggesting that it abrogates a negatively-acting regulatory element. A second C/EBPβ binding site was identified in vitro that activated the EP in vivo and whose function and location in the epithelial-specific enhancer is shown to be conserved in the highly prevalent HPV18. These results suggest that C/EBPβ is both an activator and a repressor of the HPV33 EP, acting via two distinct binding sites. Prediction of C/EBPβ sites in the LCR of 186 HPV types suggests that C/EBPβ regulation of the EP is common among high‐risk viruses from the α genus.
Combining magnetic forces for contactless manipulation of fluids in microelectrode-microfluidic systems
Authors: Haehnel Veronika , Khan Foysal Z. , Mutschke Gerd , Cierpka Christian , Uhlemann Margitta , Fritsch Ingrid 
Published: March 2019

AbstractA novel method to drive and manipulate fluid in a contactless way in a microelectrode-microfluidic system is demonstrated by combining the Lorentz and magnetic field gradient forces. The method is based on the redox-reaction [Fe(CN)6]3−/[Fe(CN)6]4− performed in a magnetic field oriented perpendicular to the ionic current that crosses the gap between two arrays of oppositely polarized microelectrodes, generating a magnetohydrodynamic flow. Additionally, a movable magnetized CoFe micro-strip is placed at different positions beneath the gap. In this region, the magnetic flux density is changed locally and a strong magnetic field gradient is formed. The redox-reaction changes the magnetic susceptibility of the electrolyte near the electrodes, and the resulting magnetic field gradient exerts a force on the fluid, which leads to a deflection of the Lorentz force-driven main flow. Particle Image Velocity measurements and numerical simulations demonstrate that by combining the two magnetic forces, the flow is not only redirected, but also a local change of concentration of paramagnetic species is realized.
Effects of Intradermal Radiofrequency Treatment and Intense Pulsed Light Therapy in an Acne-induced Rabbit Ear Model
Authors: Seok Joon , Kim Jong Hwan , Kim Jae Min , Kwon Tae Rin , Choi Sun Young , Li Kapsok , Kim Beom Joon 
Published: March 2019

AbstractAcne vulgaris is a common condition that can have psychologically deleterious effects. Since current treatments carry the risks of antibiotic resistance or teratogenicity, novel treatment modalities are under investigation. Our study investigated the efficacy of intradermal radiofrequency treatment (RF) and intense pulsed light (IPL) in the treatment of acne vulgaris in a rabbit ear model. We evaluated the effectiveness of IPL, RF, and a combination treatment on cultured Cuticobacterium acnes strains in an induced rabbit ear model, according to clinical outcomes as well as histological and immunological approaches. We found that RF treatment markedly decreases papule volume, while IPL appears to have an immunomodulatory effect. In combination, the two have an additive effect in treatment. These findings suggest that combination of RF and IPL may be an effective therapeutic option for the treatment of acne vulgaris.
Formation processes for large ejecta and interactions with melt pool formation in powder bed fusion additive manufacturing
Authors: Nassar Abdalla R. , Gundermann Molly A. , Reutzel Edward W. , Guerrier Paul , Krane Michael H. , Weldon Matthew J. 
Published: March 2019

AbstractEjecta with a size much larger than the mean particle size of feedstock powder have been observed in powder bed fusion additive manufacturing, both during post-process sieving and embedded within built components. However, their origin has not been adequately explained. Here, we test a hypothesis on the origin of large (much larger than the mass-median-diameter of feedstock powder) ejecta—that, in part, they result from stochastic, inelastic collisions of ejecta and coalescence of partially-sintered agglomerates. The hypothesis is tested using direct observation of ejecta behavior, via high-speed imaging, to identify interactions between ejecta and consequences on melt pool formation. We show that stochastic collisions occur both between particles which are nearly-simultaneously expelled from the laser interaction zone and between particles ejected from distant locations. Ejecta are also shown to perturb melt pool geometry, which is argued to be a potential cause of lack-of-fusion flaws.
Pore-forming protein complexes from Pleurotus mushrooms kill western corn rootworm and Colorado potato beetle through targeting membrane ceramide phosphoethanolamine
Authors: Panevska Anastasija , Hodnik Vesna , Skočaj Matej , Novak Maruša , Modic Špela , Pavlic Ivana , Podržaj Sara , Zarić Miki , Resnik Nataša , Maček Peter , Veranič Peter , Razinger Jaka , Sepčić Kristina 
Published: March 2019

AbstractAegerolysins ostreolysin A (OlyA) and pleurotolysin A (PlyA), and pleurotolysin B (PlyB) with the membrane-attack-complex/perforin domain are proteins from the mushroom genusPleurotus. Upon binding to sphingomyelin/cholesterol-enriched membranes, OlyA and PlyA can recruit PlyB to form multimeric bi-component transmembrane pores. Recently,Pleurotusaegerolysins OlyA, PlyA2 and erylysin A (EryA) were demonstrated to preferentially bind to artificial lipid membranes containing 50 mol% ceramide phosphoethanolamine (CPE), the main sphingolipid in invertebrate cell membranes. In this study, we demonstrate that OlyA6, PlyA2 and EryA bind to insect cells and to artificial lipid membranes with physiologically relevant CPE concentrations. Moreover, these aegerolysins permeabilize these membranes when combined with PlyB. These aegerolysin/PlyB complexes show selective toxicity toward western corn rootworm larvae and adults and Colorado potato beetle larvae. These data strongly suggest that these aegerolysin/PlyB complexes recognize CPE as their receptor molecule in the insect midgut. This mode of binding is different from those described for similar aegerolysin-based bacterial complexes, or otherBacillus thuringiensisCry toxins, which have protein receptors. Targeting ofPleurotusaegerolysins to CPE and formation of transmembrane pores in concert with PlyB suggest the use of aegerolysin/PlyB complexes as novel biopesticides for the control of western corn rootworm and Colorado potato beetle.
Novel compound mutations in the mitochondrial translation elongation factor (TSFM) gene cause severe cardiomyopathy with myocardial fibro-adipose replacement
Authors: Perli Elena , Pisano Annalinda , Glasgow Ruth I. C. , Carbo Miriam , Hardy Steven A. , Falkous Gavin , He Langping , Cerbelli Bruna , Pignataro Maria Gemma , Zacara Elisabetta , Re Federica , Della Monica Paola Lilla , Morea Veronica , Bonnen Penelope E. , Taylor Robert W. , d’Amati Giulia , Giordano Carla 
Published: March 2019

AbstractPrimary mitochondrial dysfunction is an under-appreciated cause of cardiomyopathy, especially when cardiac symptoms are the unique or prevalent manifestation of disease. Here, we report an unusual presentation of mitochondrial cardiomyopathy, with dilated phenotype and pathologic evidence of biventricular fibro-adipose replacement, in a 33-year old woman who underwent cardiac transplant. Whole exome sequencing revealed two novel compound heterozygous variants in the TSFM gene, coding for the mitochondrial translation elongation factor EF-Ts. This protein participates in the elongation step of mitochondrial translation by binding and stabilizing the translation elongation factor Tu (EF-Tu). Bioinformatics analysis predicted a destabilization of the EF-Ts variants complex with EF-Tu, in agreement with the dramatic steady-state level reduction of both proteins in the clinically affected myocardium, which demonstrated a combined respiratory chain enzyme deficiency. In patient fibroblasts, the decrease of EF-Ts was paralleled by up-regulation of EF-Tu and induction of genes involved in mitochondrial biogenesis, along with increased expression of respiratory chain subunits and normal oxygen consumption rate. Our report extends the current picture of morphologic phenotypes associated with mitochondrial cardiomyopathies and confirms the heart as a main target of TSFM dysfunction. The compensatory response detected in patient fibroblasts might explain the tissue-specific expression of TSFM-associated disease.
Position 123 of halohydrin dehalogenase HheG plays an important role in stability, activity, and enantioselectivity
Authors: Solarczek Jennifer , Klünemann Thomas , Brandt Felix , Schrepfer Patrick , Wolter Mario , Jacob Christoph R. , Blankenfeldt Wulf , Schallmey Anett 
Published: March 2019

AbstractHheG from Ilumatobacter coccineus is a halohydrin dehalogenase with synthetically useful activity in the ring opening of cyclic epoxides with various small anionic nucleophiles. This enzyme provides access to chiral β-substituted alcohols that serve as building blocks in the pharmaceutical industry. Wild-type HheG suffers from low thermostability, which poses a significant drawback for potential applications. In an attempt to thermostabilize HheG by protein engineering, several single mutants at position 123 were identified which displayed up to 14 °C increased apparent melting temperatures and up to three-fold higher activity. Aromatic amino acids at position 123 resulted even in a slightly higher enantioselectivity. Crystal structures of variants T123W and T123G revealed a flexible loop opposite to amino acid 123. In variant T123G, this loop adopted two different positions resulting in an open or partially closed active site. Classical molecular dynamics simulations confirmed a high mobility of this loop. Moreover, in variant T123G this loop adopted a position much closer to residue 123 resulting in denser packing and increased buried surface area. Our results indicate an important role for position 123 in HheG and give first structural and mechanistic insight into the thermostabilizing effect of mutations T123W and T123G.
Automatic diagnosis of neurological diseases using MEG signals with a deep neural network
Authors: Aoe Jo , Fukuma Ryohei , Yanagisawa Takufumi , Harada Tatsuya , Tanaka Masataka , Kobayashi Maki , Inoue You , Yamamoto Shota , Ohnishi Yuichiro , Kishima Haruhiko 
Published: March 2019

AbstractThe application of deep learning to neuroimaging big data will help develop computer-aided diagnosis of neurological diseases. Pattern recognition using deep learning can extract features of neuroimaging signals unique to various neurological diseases, leading to better diagnoses. In this study, we developed MNet, a novel deep neural network to classify multiple neurological diseases using resting-state magnetoencephalography (MEG) signals. We used the MEG signals of 67 healthy subjects, 26 patients with spinal cord injury, and 140 patients with epilepsy to train and test the network using 10-fold cross-validation. The trained MNet succeeded in classifying the healthy subjects and those with the two neurological diseases with an accuracy of 70.7 ± 10.6%, which significantly exceeded the accuracy of 63.4 ± 12.7% calculated from relative powers of six frequency bands (δ: 1–4 Hz; θ: 4–8 Hz; low-α: 8–10 Hz; high-α: 10–13 Hz; β: 13–30 Hz; low-γ: 30–50 Hz) for each channel using a support vector machine as a classifier (p = 4.2 × 10−2). The specificity of classification for each disease ranged from 86–94%. Our results suggest that this technique would be useful for developing a classifier that will improve neurological diagnoses and allow high specificity in identifying diseases.
A new common functional coding variant at the DDC gene change renal enzyme activity and modify renal dopamine function
Authors: Miramontes-Gonzalez Jose Pablo , Hightower C. Makena , Zhang Kuixing , Kurosaki Hiroki , Schork Andrew J. , Biswas Nilima , Vaingankar Sucheta , Mahata Manjula , Lipkowitz Michael S. , Nievergelt Caroline M. , Baker Dewleen G. , Ziegler Michael G. , León-Jiménez David , González-Sarmiento Rogelio , Ichinose Hiroshi , O’Connor Daniel T. 
Published: March 2019

AbstractThe intra-renal dopamine (DA) system is highly expressed in the proximal tubule and contributes to Na+ and blood pressure homeostasis, as well as to the development of nephropathy. In the kidney, the enzyme DOPA Decarboxylase (DDC) originating from the circulation. We used a twin/family study design, followed by polymorphism association analysis at DDC locus to elucidate heritable influences on renal DA production. Dense single nucleotide polymorphism (SNP) genotyping across the DDC locus on chromosome 7p12 was analyzed by re-sequencing guided by trait-associated genetic markers to discover the responsible genetic variation. We also characterized kinetics of the expressed DDC mutant enzyme. Systematic polymorphism screening across the 15-Exon DDC locus revealed a single coding variant in Exon-14 that was associated with DA excretion and multiple other renal traits indicating pleiotropy. When expressed and characterized in eukaryotic cells, the 462Gln variant displayed lower Vmax (maximal rate of product formation by an enzyme) (21.3 versus 44.9 nmol/min/mg) and lower Km (substrate concentration at which half-maximal product formation is achieved by an enzyme.)(36.2 versus 46.8 μM) than the wild-type (Arg462) allele. The highly heritable DA excretion trait is substantially influenced by a previously uncharacterized common coding variant (Arg462Gln) at the DDC gene that affects multiple renal tubular and glomerular traits, and predicts accelerated functional decline in chronic kidney disease.
Vascular Response to Sildenafil Citrate in Aging and Age-Related Macular Degeneration
Authors: Yiu Glenn , Vuong Vivian S. , Tran Steven , Migacz Justin , Cunefare David , Farsiu Sina , Khandelwal Neha , Agrawal Rupesh , Cheung Chui Ming Gemmy 
Published: March 2019

AbstractAge-related macular degeneration (AMD) - the leading cause of vision loss in the elderly - share many risks factors as atherosclerosis, which exhibits loss of vascular compliance resulting from aging and oxidative stress. Here, we attempt to explore choroidal and retinal vascular compliance in patients with AMD by evaluating dynamic vascular changes using live ocular imaging following treatment with oral sildenafil citrate, a phosphodiesterase type 5 (PDE5) inhibitor and potent vasodilator. Enhanced-depth imaging optical coherence tomography (EDI-OCT) and OCT angiography (OCT-A) were performed on 46 eyes of 23 subjects, including 15 patients with non-exudative AMD in one eye and exudative AMD in the fellow eye, and 8 age-matched control subjects. Choroidal thickness, choroidal vascularity, and retinal vessel density were measured across the central macula at 1 and 3 hours after a 100 mg oral dose of sildenafil citrate. Baseline choroidal thickness was 172.1 ± 60.0 μm in non-exudative AMD eyes, 196.4 ± 89.8 μm in exudative AMD eyes, and 207.4 ± 77.7 μm in control eyes, with no difference between the 3 groups (P = 0.116). After sildenafil, choroidal thickness increased by 6.0% to 9.0% at 1 and 3 hours in all groups (P = 0.001–0.014). Eyes from older subjects were associated with choroidal thinning at baseline (P = 0.005) and showed less choroidal expansion at 1 hour and 3 hours after sildenafil (P = 0.001) regardless of AMD status (P = 0.666). The choroidal thickening appeared to be primarily attributed to expansion of the stroma rather than luminal component. Retinal vascular density remained unchanged after sildenafil in all 3 groups (P = 0.281–0.587). Together, our studies suggest that vascular response of the choroid to sildenafil decreases with age, but is not affected by the presence of non-exudative or exudative AMD, providing insight into changes in vessel compliance in aging and AMD.
Minimally-verbal children with autism show deficits in theta and gamma oscillations during processing of semantically-related visual information
Authors: Ortiz-Mantilla Silvia , Cantiani Chiara , Shafer Valerie L. , Benasich April A. 
Published: March 2019

AbstractTo acquire language, children must build phonemic representations of their native language, learn to associate auditory words to visual objects and assemble a lexicon. It is not clear however, whether the limited linguistic ability seen in minimally-verbal (MV) children with Autism Spectrum Disorder (ASD) relates to deficits in cortical representation of an object and/or in linking an object to its semantic information. This EEG-based study investigated neural mechanisms underlying visual processing of common objects in MV-ASD and control children. Ten MV-ASD children, 4- to 7- years-old and 15 age/gender-matched controls, were presented with a picture-word matching paradigm. Time-frequency analyses were conducted at the sources generating the event-related responses at both early and late visual processing. Permutation testing identified spectral power and phase coherence clusters that significantly differed between the groups. As compared to controls, MV-ASD children exhibited smaller amplitudes and longer source latencies; decreased gamma and theta power with less theta phase coherence in occipital regions, and reduced frontal gamma power. Our results confirm that visual processing is altered in MV-ASD children and suggest that some of the linguistic differences observed in these children arise from impaired object/label cortical representations and reduced allocation of attention, which would impact lexical acquisition.
Frequency-specific coupling in fronto-parieto-occipital cortical circuits underlie active tactile discrimination
Authors: Kunicki Carolina , C. Moioli Renan , Pais-Vieira Miguel , Salles Cunha Peres André , Morya Edgard , A. L. Nicolelis Miguel 
Published: March 2019

AbstractProcessing of tactile sensory information in rodents is critically dependent on the communication between the primary somatosensory cortex (S1) and higher-order integrative cortical areas. Here, we have simultaneously characterized single-unit activity and local field potential (LFP) dynamics in the S1, primary visual cortex (V1), anterior cingulate cortex (ACC), posterior parietal cortex (PPC), while freely moving rats performed an active tactile discrimination task. Simultaneous single unit recordings from all these cortical regions revealed statistically significant neuronal firing rate modulations during all task phases (anticipatory, discrimination, response, and reward). Meanwhile, phase analysis of pairwise LFP recordings revealed the occurrence of long-range synchronization across the sampled fronto-parieto-occipital cortical areas during tactile sampling. Causal analysis of the same pairwise recorded LFPs demonstrated the occurrence of complex dynamic interactions between cortical areas throughout the fronto-parietal-occipital loop. These interactions changed significantly between cortical regions as a function of frequencies (i.e. beta, theta and gamma) and according to the different phases of the behavioral task. Overall, these findings indicate that active tactile discrimination by rats is characterized by much more widespread and dynamic complex interactions within the fronto-parieto-occipital cortex than previously anticipated.