bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical whole genome sequencing as a first-tier test at a resource-limited dysmorphology clinic in Mexico
Authors: Scocchia Alicia , Wigby Kristen M. , Masser-Frye Diane , Del Campo Miguel , Galarreta Carolina I. , Thorpe Erin , McEachern Julia , Robinson Keisha , Gross Andrew ,   ICSL Interpretation and Reporting Team, Bennett Maren , Bluske Krista , Brown Carolyn M. , Buchanan Amanda , Burns Brendan , Burns Nicole J. , Chandrasekhar Anjana , Chawla Aditi , Clause Amanda R. , Coffey Alison J. , Cremona Maria Laura , Gainullin Vlad , Hagelstrom R. Tanner , Malhotra Alka , Rajan Maya , Rajkumar Revathi , Schmidt Sarah , Ajay Subramanian S. , Rajan Vani , Perry Denise L. , Belmont John W. , Bentley David R. , Jones Marilyn C. , Taft Ryan J. 
Published: February 2019

AbstractPatients with rare, undiagnosed, or genetic disease (RUGD) often undergo years of serial testing, commonly referred to as the “diagnostic odyssey”. Patients in resource-limited areas face even greater challenges—a definitive diagnosis may never be reached due to difficulties in gaining access to clinicians, appropriate specialists, and diagnostic testing. Here, we report on a collaboration of the Illumina iHope Program with the Foundation for the Children of the Californias and Hospital Infantil de Las Californias, to enable deployment of clinical whole genome sequencing (cWGS) as first-tier test in a resource-limited dysmorphology clinic in northern Mexico. A total of 60 probands who were followed for a suspected genetic diagnosis and clinically unresolved after expert examination were tested with cWGS, and the ordering clinicians completed a semi-structured survey to investigate change in clinical management resulting from cWGS findings. Clinically significant genomic findings were identified in 68.3% (n = 41) of probands. No recurrent molecular diagnoses were observed. Copy number variants or gross chromosomal abnormalities accounted for 48.8% (n = 20) of the diagnosed cases, including a mosaic trisomy and suspected derivative chromosomes. A qualitative assessment of clinical management revealed 48.8% (n = 20) of those diagnosed had a change in clinical course based on their cWGS results, despite resource limitations. These data suggest that a cWGS first-tier testing approach can benefit patients with suspected genetic disorders.
Protein–Protein Affinity Determination by Quantitative FRET Quenching
Authors: Jiang Ling , Xiong Zhehao , Song Yang , Lu Yanrong , Chen Younan , Schultz Jerome S. , Li Jun , Liao Jiayu 
Published: February 2019

AbstractThe molecular dissociation constant, Kd, is a well-established parameter to quantitate the affinity of protein-protein or other molecular interactions. Recently, we reported the theoretical basis and experimental procedure for Kd determination using a quantitative FRET method. Here we report a new development of Kd determination by measuring the reduction in donor fluorescence due to acceptor quenching in FRET. A new method of Kd determination was developed from the quantitative measurement of donor fluorescence quenching. The estimated Kd values of SUMO1-Ubc9 interaction based on this method are in good agreement with those determined by other technologies, including FRET acceptor emission. Thus, the acceptor-quenched approach can be used as a complement to the previously developed acceptor excitation method. The new methodology has more general applications regardless whether the acceptor is an excitable fluorophore or a quencher. Thus, these developments provide a complete methodology for protein or other molecule interaction affinity determinations in solution.
Insights into the biogenesis and potential functions of exonic circular RNA
Authors: Ragan Chikako , Goodall Gregory J. , Shirokikh Nikolay E. , Preiss Thomas 
Published: February 2019

AbstractCircular RNAs (circRNAs) exhibit unique properties due to their covalently closed nature. Models of circRNAs synthesis and function are emerging but much remains undefined about this surprisingly prevalent class of RNA. Here, we identified exonic circRNAs from human and mouse RNA-sequencing datasets, documenting multiple new examples. Addressing function, we found that many circRNAs co-sediment with ribosomes, indicative of their translation potential. By contrast, circRNAs with potential to act as microRNA sponges were scarce, with some support for a collective sponge function by groups of circRNAs. Addressing circRNA biogenesis, we delineated several features commonly associated with circRNA occurrence. CircRNA-producing genes tend to be longer and to contain more exons than average. Back-splice acceptor exons are strongly enriched at ordinal position 2 within genes, and circRNAs typically have a short exon span with two exons being the most prevalent. The flanking introns either side of circRNA loci are exceptionally long. Of note also, single-exon circRNAs derive from unusually long exons while multi-exon circRNAs are mostly generated from exons of regular length. These findings independently validate and extend similar observations made in a number of prior studies. Furthermore, we analysed high-resolution RNA polymerase II occupancy data from two separate human cell lines to reveal distinctive transcription dynamics at circRNA-producing genes. Specifically, RNA polymerase II traverses the introns of these genes at above average speed concomitant with an accentuated slow-down at exons. Collectively, these features indicate how a perturbed balance between transcription and linear splicing creates important preconditions for circRNA production. We speculate that these preconditions need to be in place so that looping interactions between flanking introns can promote back-splicing to raise circRNA production to appreciable levels.
Nutritional and lipidomics biomarkers of docosahexaenoic acid-based multivitamin therapy in pediatric NASH
Authors: Torquato Pierangelo , Giusepponi Danilo , Alisi Anna , Galarini Roberta , Bartolini Desirée , Piroddi Marta , Goracci Laura , Di Veroli Alessandra , Cruciani Gabriele , Crudele Annalisa , Nobili Valerio , Galli Francesco 
Published: February 2019

AbstractTwo recent randomized controlled trials demonstrated improved radiographic, histological and hepatometabolic cues of non-alcoholic steatohepatitis (NASH) in pediatric patients treated with the ω-3 fatty acid docosahexaenoic acid (DHA) in combination with vitamin D (VD) or with choline (CHO) and vitamin E (VE), the DHA-VD and DHA-CHO-VE trials, respectively). In the present study we verified the nutritional compliance to these DHA-based multivitamin treatments; lipidomics biomarkers of the reported outcome on NASH indicators were also investigated. Samples were obtained from 30 biopsy-proven pediatric NASH patients of the DHA-CHO-VE trial randomized in multivitamin treatment group and placebo group (n = 15 each), and from 12 patients of the treatment group of the DHA-VD trial. All patients underwent 6-month therapy plus 6 months of follow-up. Plasma samples and clinical data were obtained at baseline and at the end of the study (12 months). Selected biomarkers included the free form of DHA and other ω-3 fatty acid arachidonic acid (AA), indices of the vitamin E status, and some hepatic metabolites of these lipids. Radiographic and histological improvements of treated patients were associated with increased concentrations of DHA, α-linolenic acid and α-tocopherol (i.e. VE), and with decreased AA that was also investigated in complex lipids by untargetd lipidomics. As a result a significantly lowered AA/DHA ratio was observed to represent the main indicator of the response to the DHA-based therapy. Furthermore, baseline levels of AA/DHA showed strong association with NAS and US improvement. A stable correction of DHA AA metabolism interaction is associated with the curative effect of this therapy and may represent a key nutritional endpoint in the clinical management of pediatric NASH.
LIM homeobox 2 promotes interaction between human iPS-derived hepatic progenitors and iPS-derived hepatic stellate-like cells
Authors: Miyoshi Masato , Kakinuma Sei , Kamiya Akihide , Tsunoda Tomoyuki , Tsuchiya Jun , Sato Ayako , Kaneko Shun , Nitta Sayuri , Kawai-Kitahata Fukiko , Murakawa Miyako , Itsui Yasuhiro , Nakagawa Mina , Azuma Seishin , Nakauchi Hiromitsu , Asahina Yasuhiro , Watanabe Mamoru 
Published: February 2019

AbstractHuman induced pluripotent stem (iPS) cells can differentiate into hepatocyte lineages, although the phenotype of the differentiated cells is immature compared to adult hepatocytes. Improvement of cell-cell interactions between epithelium and mesenchyme is a potential approach to address this phenotype issue. In this study, we developed a model system for improving interactions between human iPS-derived hepatic progenitor cells (iPS-HPCs) and human iPS-derived hepatic stellate cell-like cells (iPS-HSCs). The phenotype of iPS-HSCs, including gene and protein expression profiles and vitamin A storage, resembled that of hepatic stellate cells. Direct co-culture of iPS-HSCs with iPS-HPCs significantly improved hepatocytic maturation in iPS-HPCs, such as their capacity for albumin production. Next, we generated iPS cell lines overexpressing LIM homeobox 2 (LHX2), which suppresses myofibroblastic changes in HSCs in mice. Hepatocytic maturation in iPS-HPCs was significantly increased in direct co-culture with iPS-HSCs overexpressing LHX2, but not in co-culture with a human hepatic stellate cell line (LX-2) overexpressing LHX2. LHX2 regulated the expression of extracellular matrices, such as laminin and collagen, in iPS-HSCs. In conclusion, this study provides an evidence that LHX2 upregulation in iPS-HSCs promotes hepatocytic maturation of iPS-HPCs, and indicates that genetically modified iPS-HSCs will be of value for research into cell-cell interactions.
Enhanced anti-tumor activity of the Multi-Leu peptide PACE4 inhibitor transformed into an albumin-bound tumor-targeting prodrug
Authors: Kwiatkowska Anna , Couture Frédéric , Ait-Mohand Samia , Desjardins Roxane , Dory Yves L. , Guérin Brigitte , Day Robert 
Published: February 2019

AbstractThe proprotein convertase PACE4 has been validated as a potential target to develop new therapeutic interventions in prostate cancer (PCa). So far, the most effective compound blocking the activity of this enzyme has been designed based on the structure of a small peptide Ac-LLLLRVKR-NH2 known as the Multi-Leu (ML) peptide. Optimization of this scaffold led to the synthesis of compound C23 (Ac-[DLeu]LLLRVK-amidinobenzylamide) with a potent in vivo inhibitory effect on the tumor growth. However, further developments of PACE4 inhibitors may require additional improvements to counter their rapid renal clearance and to increase their tumor targeting efficiency. Herein, we explored the transformation of the ML-peptide into an albumin-binding prodrug containing a tumor specific release mechanism based on the prostate-specific antigen. Our data confirms that intravenous treatment using the ML-peptide alone has little effect on tumor growth, whereas by using the ML-prodrug in LNCaP xenograft-bearing mice it was significantly reduced. Additionally, excellent in vivo stability and tumor-targeting efficiency was demonstrated using a radiolabelled version of this compound. Taken together, these results provide a solid foundation for further development of targeted PACE4 inhibition in PCa.
Electroceutical Treatment of Pseudomonas aeruginosa Biofilms
Authors: Dusane Devendra H. , Lochab Varun , Jones Travis , Peters Casey W. , Sindeldecker Devin , Das Amitava , Roy Sashwati , Sen Chandan K. , Subramaniam Vish V. , Wozniak Daniel J. , Prakash Shaurya , Stoodley Paul 
Published: February 2019

AbstractElectroceutical wound dressings, especially those involving current flow with silver based electrodes, show promise for treating biofilm infections. However, their mechanism of action is poorly understood. We have developed an in vitro agar based model using a bioluminescent strain of Pseudomonas aeruginosa to measure loss of activity and killing when direct current was applied. Silver electrodes were overlaid with agar and lawn biofilms grown for 24 h. A 6 V battery with 1 kΩ ballast resistor was used to treat the biofilms for 1 h or 24 h. Loss of bioluminescence and a 4-log reduction in viable cells was achieved over the anode. Scanning electron microscopy showed damaged cells and disrupted biofilm architecture. The antimicrobial activity continued to spread from the anode for at least 2 days, even after turning off the current. Based on possible electrochemical ractions of silver electrodes in chlorine containing medium; pH measurements of the medium post treatment; the time delay between initiation of treatment and observed bactericidal effects; and the presence of chlorotyrosine in the cell lysates, hypochlorous acid is hypothesized to be the chemical agent responsible for the observed (destruction/killing/eradication) of these biofilm forming bacteria. Similar killing was obtained with gels containing only bovine synovial fluid or human serum. These results suggest that our in vitro model could serve as a platform for fundamental studies to explore the effects of electrochemical treatment on biofilms, complementing clinical studies with electroceutical dressings.
A Surface Plasmon Resonance-based assay to measure serum concentrations of therapeutic antibodies and anti-drug antibodies
Authors: Beeg Marten , Nobili Alessandro , Orsini Barbara , Rogai Francesca , Gilardi Daniela , Fiorino Gionata , Danese Silvio , Salmona Mario , Garattini Silvio , Gobbi Marco 
Published: February 2019

AbstractTherapeutic drug and immunogenicity monitoring (TDIM) is increasingly proposed to guide therapy with biologics, characterised by high inter-individual variability of their blood levels, to permit objective decisions for the management of non-responders and reduce unnecessary interventions with these expensive treatments. However, TDIM has not yet entered clinical practice partly because of uncertainties regarding the accuracy and precision of enzyme-linked immunosorbent assays (ELISA). Here we report the characterisation of a novel surface plasmon resonance (SPR)-based TDIM, applied to the measurement of serum concentrations of infliximab, an antibody against tumour necrosis factor α (anti-TNFα), and anti-infliximab antibodies. SPR has the obvious advantages of directly detecting and measuring serum antibodies in minutes, avoiding the long incubation/separation/washing/detection steps of the methods proposed so far, reducing complexity and variability. Moreover, drug and anti-drug antibodies can be measured simultaneously. This new method was validated for sensitivity and reproducibility, and showed cost-effectiveness over commercial ELISA kits. This method may be applied to other biotherapeutics. These data pave the way for the development of SPR-based point-of-care devices for rapid on-site analysis.
Asymmetric controlled bidirectional remote preparation of two- and three-qubit equatorial state
Authors: Sun Yi-Ru , Chen Xiu-Bo , Xu Gang , Yuan Kai-Guo , Yang Yi-Xian 
Published: February 2019

AbstractIn this paper, a novel asymmetric controlled bidirectional remote preparation scheme is proposed. In our scheme, Alice and Bob are not only the senders but also the receivers with the control of Charlie. By using the eleven-qubit entangled state as the quantum channel, Alice prepares an arbitrary two-qubit equatorial state for Bob and Bob prepares an arbitrary three-qubit equatorial state for Alice simultaneously. Firstly, we give the construction process of the quantum channel. Secondly, the whole recovery operations are given. Alice and Bob can recover the prepared state determinately. Thirdly, we consider the effect of the noisy environment (amplitude-damping and phase-damping) in our scheme and calculate the fidelities of the output states. Finally, since our scheme does not need additional operations and auxiliary qubits, the efficiency of our scheme is higher than that of the previous schemes.
Combining Multiple Magnetic Resonance Imaging Sequences Provides Independent Reproducible Radiomics Features
Authors: Lecler A. , Duron L. , Balvay D. , Savatovsky J. , Bergès O. , Zmuda M. , Farah E. , Galatoire O. , Bouchouicha A. , Fournier L. S. 
Published: February 2019

AbstractTo evaluate the relative contribution of different Magnetic Resonance Imaging (MRI) sequences for the extraction of radiomics features in a cohort of patients with lacrimal gland tumors. This prospective study was approved by the Institutional Review Board and signed informed consent was obtained from all participants. From December 2015 to April 2017, 37 patients with lacrimal gland lesions underwent MRI before surgery, including axial T1-WI, axial Diffusion-WI, coronal DIXON-T2-WI and coronal post-contrast DIXON-T1-WI. Two readers manually delineated both lacrimal glands to assess inter-observer reproducibility, and one reader performed two successive delineations to assess intra-observer reproducibility. Radiomics features were extracted using an in-house software to calculate 85 features per region-of-interest (510 features/patient). Reproducible features were defined as features presenting both an intra-class correlation coefficient ≥0.8 and a concordance correlation coefficient ≥0.9 across combinations of the three delineations. Among these features, the ones yielding redundant information were identified as clusters using hierarchical clustering based on the Spearman correlation coefficient. All the MR sequences provided reproducible radiomics features (range 14(16%)−37(44%)) and non-redundant clusters (range 5–14). The highest numbers of features and clusters were provided by the water and in-phase DIXON T2-WI and water and in-phase post-contrast DIXON T1-WI (37, 26, 26 and 26 features and 14,12, 9 and 11 clusters, respectively). A total of 145 reproducible features grouped into 51 independent clusters was provided by pooling all the MR sequences. All MRI sequences provided reproducible radiomics features yielding independent information which could potentially serve as biomarkers.
Multi Band Gap Electronic Structure in CH3NH3PbI3
Authors: Ong Khuong P. , Wu Shunnian , Nguyen Tien Hoa , Singh David J. , Fan Zhen , Sullivan Michael B. , Dang Cuong 
Published: February 2019

AbstractOrgano-lead halide perovskite solar cells represent a revolutionary shift in solar photovoltaics, introducing relatively soft defect containing semiconductors as materials with excellent charge collection for both electrons and holes. Although they are based on the nominally simple cubic perovskite structure, these compounds are in fact very complex. For example, in (CH3NH3)PbI3 the dynamics and ensuing structural fluctuations associated with the (CH3NH3)+ ions and the interplay with the electronic properties are still not fully understood, despite extensive study. Here, using ab-initio calculations, we show that at room and higher temperature, the rotation of CH3NH3 molecules can be viewed as effectively giving local structures that are cubic and tetragonal like from the point of view of the PbI3 framework, though in fact having lower symmetry. Both of these structures are locally polar, with sizable polarization, ~10 μC/cm2 due to the dipoles on the organic. They become energetically degenerate in the volume range, V ~ 250 Å3/f.u–265 Å3/f.u. We also find very significant dependence of the band gap on the local structure. This type of transition is analogous to a transition between two ferroelectric structures, where in-spite of strong electron phonon coupling, there is strong screening of charged defects which can lead to enhanced mobility and charge collection. The results provide insights into the enhanced light absorption near the band edge and good charge collection in this material.
PDGF-BB serum levels are decreased in adult onset Pompe patients
Authors: Fernández-Simón Esther , Carrasco-Rozas Ana , Gallardo Eduard , Figueroa-Bonaparte Sebastián , Belmonte Izaskun , Pedrosa Irene , Montiel Elena , Suárez-Calvet Xavier , Alonso-Pérez Jorge , Segovia Sonia , Nuñez-Peralta Claudia , Llauger Jaume , Mayos Mercedes , Illa Isabel ,   Spanish Pompe Study Group, Barba-Romero Miguel Angel , Barcena Joseba , Carzorla María Rosario , Creus Carlota , Coll-Cantí Jaume , de Luna Noemí , Díaz Manuel , Domínguez Cristina , Fernández-Torrón Roberto , García-Antelo María José , Grau Josep María , Gómez-Caravaca María Teresa , León-Hernández Juan Carlos , López de Munáin Adolfo , Martínez-García Francisco Antonio , Morgado Yolanda , Moreno Antonio , Morís Germán , Muñoz-Blanco Miguel Angel , Nascimento Andres , Paradas Carmen , Parajuá-Pozo José Luis , Querol Luis , Robledo-Strauss Arturo , Rojas-García Ricard , Rojas-Marcos Íñigo , Salazar Jose Antonio , Usón Mercedes , Díaz-Manera Jordi 
Published: February 2019

AbstractAdult onset Pompe disease is a genetic disorder characterized by slowly progressive skeletal and respiratory muscle weakness. Symptomatic patients are treated with enzymatic replacement therapy with human recombinant alfa glucosidase. Motor functional tests and spirometry are commonly used to follow patients up. However, a serological biomarker that correlates with the progression of the disease could improve follow-up. We studied serum concentrations of TGFβ, PDGF-BB, PDGF-AA and CTGF growth factors in 37 adult onset Pompe patients and 45 controls. Moreover, all patients performed several muscle function tests, conventional spirometry, and quantitative muscle MRI using 3-point Dixon. We observed a statistically significant change in the serum concentration of each growth factor in patients compared to controls. However, only PDGF-BB levels were able to differentiate between asymptomatic and symptomatic patients, suggesting its potential role in the follow-up of asymptomatic patients. Moreover, our results point to a dysregulation of muscle regeneration as an additional pathomechanism of Pompe disease.
Detection of ‘Candidatus Phytoplasma solani’ in roots from Bois noir symptomatic and recovered grapevines
Authors: Landi Lucia , Murolo Sergio , Romanazzi Gianfranco 
Published: February 2019

Abstract‘Candidatus Phytoplasma solani’ is the causal agent of Bois noir (BN) in grapevine (Vitis vinifera). It is usually detected in leaves, where typical disease symptoms are seen. However, little information is available on the presence of this phytoplasma in grapevine roots. Here, we investigated ‘Ca. P. solani’ in roots collected from 28 symptomatic, 27 recovered and eight asymptomatic grapevine plants. Protocols based on high-resolution melting (HRM) combined with real-time quantitative PCR (qPCR-HRM) and nested-qPCR-HRM were developed to identify ‘Ca. P. solani’ tuf-type variants with single nucleotide polymorphisms. In all, 21.4% of roots from symptomatic plants were positive to ‘Ca. P. solani’ using qPCR-HRM, and 60.7% with nested-qPCR HRM. Also, 7.4% of roots from recovered plants were positive using qPCR-HRM, which reached 44.4% using nested-qPCR HRM. These analyses identified tuf-type b1 on 88.2% of the positive samples from symptomatic grapevines, and 66.6% from recovered grapevines, with all other samples identified as tuf-type a. This study reports the presence of ‘Ca. P. solani’ in the roots of both symptomatic and recovered grapevines. These qPCR-HRM and nested-qPCR-HRM protocols can be applied to increase the sensitivity of detection of, and to simplify and speed up the screening for, ‘Ca. P. solani’ tuf-types.