bluuebunny/crossref_metadata_2025_split huggingface dataset:
An individualized immune signature of pretreatment biopsies predicts pathological complete response to neoadjuvant chemoradiotherapy and outcomes in patients with esophageal squamous cell carcinoma
Authors: Zhang Chaoqi , Zhang Guochao , Sun Nan , Zhang Zhen , Xue Liyan , Zhang Zhihui , Yang Haijun , Luo Yuejun , Zheng Xiaoli , Zhang Yonglei , Yuan Yufen , Lei Ruixue , Yang Zhaoyang , Zheng Bo , Wang Le , Che Yun , Wang Feng , Wang Sihui , Gao Shugeng , Xue Qi , Zhang Yi , He Jie 
Published: September 2020

AbstractNo clinically available biomarkers can predict pathological complete response (pCR) for esophageal squamous cell carcinomas (ESCCs) with neoadjuvant chemoradiotherapy (nCRT). Considering that antitumor immunity status is an important determinant for nCRT, we performed an integrative analysis of immune-related gene profiles from pretreatment biopsies and constructed the first individualized immune signature for pCR and outcome prediction of ESCCs through a multicenter analysis. During the discovery phase, 14 differentially expressed immune-related genes (DEIGs) with greater than a twofold change between pCRs and less than pCRs (<pCRs) were revealed from 28 pretreatment tumors in a Guangzhou cohort using microarray data. Ten DEIGs were verified by qPCR from 30 cases in a Beijing discovery cohort. Then, a four-gene-based immune signature (SERPINE1, MMP12, PLAUR, and EPS8) was built based on the verified DEIGs from 71 cases in a Beijing training cohort, and achieved a high accuracy with an area under the receiver operating characteristic curve (AUC) of 0.970. The signature was further validated in an internal validation cohort and an integrated external cohort (Zhengzhou and Anyang cohorts) with AUCs of 0.890 and 0.859, respectively. Importantly, a multivariate analysis showed that the signature was the only independent predictor for pCR. In addition, patients with high predictive scores showed significantly longer overall and relapse-free survival across multiple centers (P < 0.05). This is the first, validated, and clinically applicable individualized immune signature of pCR and outcome prediction for ESCCs with nCRT. Further prospective validation may facilitate the combination of nCRT and immunotherapy.
An alpaca nanobody neutralizes SARS-CoV-2 by blocking receptor interaction
Authors: Hanke Leo , Vidakovics Perez Laura , Sheward Daniel J. , Das Hrishikesh , Schulte Tim , Moliner-Morro Ainhoa , Corcoran Martin , Achour Adnane , Karlsson Hedestam Gunilla B. , Hällberg B. Martin , Murrell Ben , McInerney Gerald M. 
Published: September 2020

AbstractSARS-CoV-2 enters host cells through an interaction between the spike glycoprotein and the angiotensin converting enzyme 2 (ACE2) receptor. Directly preventing this interaction presents an attractive possibility for suppressing SARS-CoV-2 replication. Here, we report the isolation and characterization of an alpaca-derived single domain antibody fragment, Ty1, that specifically targets the receptor binding domain (RBD) of the SARS-CoV-2 spike, directly preventing ACE2 engagement. Ty1 binds the RBD with high affinity, occluding ACE2. A cryo-electron microscopy structure of the bound complex at 2.9 Å resolution reveals that Ty1 binds to an epitope on the RBD accessible in both the ‘up’ and ‘down’ conformations, sterically hindering RBD-ACE2 binding. While fusion to an Fc domain renders Ty1 extremely potent, Ty1 neutralizes SARS-CoV-2 spike pseudovirus as a 12.8 kDa nanobody, which can be expressed in high quantities in bacteria, presenting opportunities for manufacturing at scale. Ty1 is therefore an excellent candidate as an intervention against COVID-19.
Both Boceprevir and GC376 efficaciously inhibit SARS-CoV-2 by targeting its main protease
Authors: Fu Lifeng , Ye Fei , Feng Yong , Yu Feng , Wang Qisheng , Wu Yan , Zhao Cheng , Sun Huan , Huang Baoying , Niu Peihua , Song Hao , Shi Yi , Li Xuebing , Tan Wenjie , Qi Jianxun , Gao George Fu 
Published: September 2020

AbstractCOVID-19 was declared a pandemic on March 11 by WHO, due to its great threat to global public health. The coronavirus main protease (Mpro, also called 3CLpro) is essential for processing and maturation of the viral polyprotein, therefore recognized as an attractive drug target. Here we show that a clinically approved anti-HCV drug, Boceprevir, and a pre-clinical inhibitor against feline infectious peritonitis (corona) virus (FIPV), GC376, both efficaciously inhibit SARS-CoV-2 in Vero cells by targeting Mpro. Moreover, combined application of GC376 with Remdesivir, a nucleotide analogue that inhibits viral RNA dependent RNA polymerase (RdRp), results in sterilizing additive effect. Further structural analysis reveals binding of both inhibitors to the catalytically active side of SARS-CoV-2 protease Mpro as main mechanism of inhibition. Our findings may provide critical information for the optimization and design of more potent inhibitors against the emerging SARS-CoV-2 virus.
Serotype specific epitopes identified by neutralizing antibodies underpin immunogenic differences in Enterovirus B
Authors: Wang Kang , Zheng Binyang , Zhang Li , Cui Lunbiao , Su Xuan , Zhang Qian , Guo Zhenxi , Guo Yu , Zhang Wei , Zhu Ling , Zhu Fengcai , Rao Zihe , Wang Xiangxi 
Published: September 2020

AbstractEchovirus 30 (E30), a serotype of Enterovirus B (EV-B), recently emerged as a major causative agent of aseptic meningitis worldwide. E30 is particularly devastating in the neonatal population and currently no vaccine or antiviral therapy is available. Here we characterize two highly potent E30-specific monoclonal antibodies, 6C5 and 4B10, which efficiently block binding of the virus to its attachment receptor CD55 and uncoating receptor FcRn. Combinations of 6C5 and 4B10 augment the sum of their individual anti-viral activities. High-resolution structures of E30-6C5-Fab and E30-4B10-Fab define the location and nature of epitopes targeted by the antibodies. 6C5 and 4B10 engage the capsid loci at the north rim of the canyon and in-canyon, respectively. Notably, these regions exhibit antigenic variability across EV-Bs, highlighting challenges in development of broad-spectrum antibodies. Our structures of these neutralizing antibodies of E30 are instructive for development of vaccines and therapeutics against EV-B infections.
Next-generation sequencing of newborn screening genes: the accuracy of short-read mapping
Authors: Trier C. , Fournous G. , Strand J. M. , Stray-Pedersen A. , Pettersen R. D. , Rowe A. D. 
Published: September 2020

AbstractNewborn screening programs are an integral part of public health systems aiming to save lives and improve the quality of life for infants with treatable disorders. Technological advancements have driven the expansion of newborn screening programs in the last two decades and the development of fast, accurate next-generation sequencing technology has opened the door to a range of possibilities in the field. However, technological challenges with short-read next-generation sequencing technologies remain significant in highly homologous genomic regions such as pseudogenes or paralogous genes and need to be considered when implemented in screening programs. Here, we simulate 50 genomes from populations around the world to test the extent to which high homology regions affect short-read mapping of genes related to newborn screening disorders and the impact of differential read lengths and ethnic backgrounds. We examine a 158 gene screening panel directly relevant to newborn screening and identify gene regions where read mapping is affected by homologous genomic regions at different read lengths. We also determine that the patient’s ethnic background does not have a widespread impact on mapping accuracy or coverage. Additionally, we identify newborn screening genes where alternative forms of sequencing or variant calling pipelines should be considered and demonstrate that alterations to standard variant calling can retrieve some formerly uncalled variants.
A multimodal magnetoencephalography 7 T fMRI and 7 T proton MR spectroscopy study in first episode psychosis
Authors: Gawne Timothy J. , Overbeek Gregory J. , Killen Jeffery F. , Reid Meredith A. , Kraguljac Nina V. , Denney Thomas S. , Ellis Charles A. , Lahti Adrienne C. 
Published: September 2020

AbstractWe combined magnetoencephalography (MEG), 7 T proton magnetic resonance spectroscopy (MRS), and 7 T fMRI during performance of a task in a group of 23 first episode psychosis (FEP) patients and 26 matched healthy controls (HC). We recorded both the auditory evoked response to 40 Hz tone clicks and the resting state in MEG. Neurometabolite levels were obtained from the anterior cingulate cortex (ACC). The fMRI BOLD response was obtained during the Stroop inhibitory control task. FEP showed a significant increase in resting state low frequency theta activity (p < 0.05; Cohen d = 0.69), but no significant difference in the 40 Hz auditory evoked response compared to HC. An across-groups whole brain analysis of the fMRI BOLD response identified eight regions that were significantly activated during task performance (p < 0.01, FDR-corrected); the mean signal extracted from those regions was significantly different between the groups (p = 0.0006; d = 1.19). In the combined FEP and HC group, there was a significant correlation between the BOLD signal during task performance and MEG resting state low frequency activity (p < 0.05). In FEP, we report significant alteration in resting state low frequency MEG activity, but no alterations in auditory evoked gamma band response, suggesting that the former is a more robust biomarker of early psychosis. There were no correlations between gamma oscillations and GABA levels in either HC or FEP. Finally, in this study, each of the three imaging modalities differentiated FEP from HC; fMRI with good and MEG and MRS with moderate effect size.
Proteins involved in the endoplasmic reticulum stress are modulated in synovitis of osteoarthritis, chronic pyrophosphate arthropathy and rheumatoid arthritis, and correlate with the histological inflammatory score
Authors: de Seny Dominique , Bianchi Elettra , Baiwir Dominique , Cobraiville Gaël , Collin Charlotte , Deliège Mégane , Kaiser Marie-Joëlle , Mazzucchelli Gabriel , Hauzeur Jean-Philippe , Delvenne Philippe , Malaise Michel G. 
Published: September 2020

AbstractIt is now well recognized that osteoarthritis (OA) synovial membrane presents inflammatory components. The aim of this work is to provide evidence that similar inflammatory mechanisms exist in synovial membrane (n = 24) obtained from three pathologies presenting altogether an inflammatory gradient: OA, chronic pyrophosphate arthropathy (CPPA) and rheumatoid arthritis (RA). Synovial biopsies were first characterized by a histological score based on synovial hyperplasia and infiltration of lymphocytes, plasma cells, polymorphonuclear and macrophages. All biopsies were also analyzed by 2D-nano-UPLC-ESI-Q-Orbitrap for protein identification and quantification. Protein levels were correlated with the histological score. Histological score was in the range of 3 to 8 for OA, 5 to 13 for CPPA and 12 to 17 for RA. Of the 4,336 proteins identified by mass spectrometry, 51 proteins were selected for their strong correlation (p < 0.001) with the histological score of which 11 proteins (DNAJB11, CALR, ERP29, GANAB, HSP90B1, HSPA1A, HSPA5, HYOU1, LMAN1, PDIA4, and TXNDC5) were involved in the endoplasmic reticulum (ER) stress. Protein levels of S100A8 and S100A9 were significantly higher in RA compared to OA (for both) or to CPPA (for S100A8 only) and also significantly correlated with the histological score. Eighteen complement component proteins were identified, but only C1QB and C1QBP were weakly correlated with the histological score. This study highlights the inflammatory gradient existing between OA, CPPA and RA synovitis either at the protein level or at the histological level. Inflamed synovitis was characterized by the overexpression of ER stress proteins.
Impact of DNA extraction on whole genome sequencing analysis for characterization and relatedness of Shiga toxin-producing Escherichia coli isolates
Authors: Nouws Stéphanie , Bogaerts Bert , Verhaegen Bavo , Denayer Sarah , Piérard Denis , Marchal Kathleen , Roosens Nancy H. C. , Vanneste Kevin , De Keersmaecker Sigrid C. J. 
Published: September 2020

AbstractWhole genome sequencing (WGS) has proven to be the ultimate tool for bacterial isolate characterization and relatedness determination. However, standardized and harmonized workflows, e.g. for DNA extraction, are required to ensure robust and exchangeable WGS data. Data sharing between (inter)national laboratories is essential to support foodborne pathogen control, including outbreak investigation. This study evaluated eight commercial DNA preparation kits for their potential influence on: (i) DNA quality for Nextera XT library preparation; (ii) MiSeq sequencing (data quality, read mapping against plasmid and chromosome references); and (iii) WGS data analysis, i.e. isolate characterization (serotyping, virulence and antimicrobial resistance genotyping) and phylogenetic relatedness (core genome multilocus sequence typing and single nucleotide polymorphism analysis). Shiga toxin-producing Escherichia coli (STEC) was selected as a case study. Overall, data quality and inferred phylogenetic relationships between isolates were not affected by the DNA extraction kit choice, irrespective of the presence of confounding factors such as EDTA in DNA solution buffers. Nevertheless, completeness of STEC characterization was, although not substantially, influenced by the plasmid extraction performance of the kits, especially when using Nextera XT library preparation. This study contributes to addressing the WGS challenges of standardizing protocols to support data portability and to enable full exploitation of its potential.
Sub-nanoscale atom-by-atom crafting of skyrmion-defect interaction profiles
Authors: Arjana I. Gede , Lima Fernandes Imara , Chico Jonathan , Lounis Samir 
Published: September 2020

AbstractMagnetic skyrmions are prime candidates as information carriers for spintronic devices due to their topological nature and nanometric size. However, unavoidable inhomogeneities inherent to any material leads to pinning or repulsion of skyrmions that, in analogy to biology concepts, define the phenotype of the skyrmion-defect interaction, generating complexity in their motion and challenging their application as future bits of information. Here, we demonstrate that atom-by-atom manufacturing of multi-atomic defects, being antiferromagnetic or ferromagnetic, permits the breeding of their energy profiles, for which we build schematically a Punnet-square. As established from first-principles for skyrmions generated in PdFe bilayer on Ir(111) surface, the resulting interaction phenotype is rich. It can be opposite to the original one and eventually be of dual pinning-repulsive nature yielding energy landscapes hosting multi-domains. This is dictated by the stacking site, geometry, size and chemical nature of the adsorbed defects, which control the involved magnetic interactions. This work provides new insights towards the development of disruptive device architectures incorporating defects into their design aiming to control and guide skyrmions.
Systems-level differential gene expression analysis reveals new genetic variants of oral cancer
Authors: Abbas Syeda Zahra , Qadir Muhammad Imran , Muhammad Syed Aun 
Published: September 2020

AbstractOral cancer (OC) ranked as eleventh malignancy worldwide, with the increasing incidence among young patients. Limited understanding of complications in cancer progression, its development system, and their interactions are major restrictions towards the progress of optimal and effective treatment strategies. The system-level approach has been designed to explore genetic complexity of the disease and to identify novel oral cancer related genes to detect genomic alterations at molecular level, through cDNA differential analysis. We analyzed 21 oral cancer-related cDNA datasets and listed 30 differentially expressed genes (DEGs). Among 30, we found 6 significant DEGs including CYP1A1, CYP1B1, ADCY2, C7, SERPINB5, and ANAPC13 and studied their functional role in OC. Our genomic and interactive analysis showed significant enrichment of xenobiotics metabolism, p53 signaling pathway and microRNA pathways, towards OC progression and development. We used human proteomic data for post-translational modifications to interpret disease mutations and inter-individual genetic variations. The mutational analysis revealed the sequence predicted disordered region of 14%, 12.5%, 10.5% for ADCY2, CYP1B1, and C7 respectively. The MiRNA target prediction showed functional molecular annotation including specific miRNA-targets hsa-miR-4282, hsa-miR-2052, hsa-miR-216a-3p, for CYP1B1, C7, and ADCY2 respectively associated with oral cancer. We constructed the system level network and found important gene signatures. The drug-gene interaction of OC source genes with seven FDA approved OC drugs help to design or identify new drug target or establishing novel biomedical linkages regarding disease pathophysiology. This investigation demonstrates the importance of system genetics for identifying 6 OC genes (CYP1A1, CYP1B1, ADCY2, C7, SERPINB5, and ANAPC13) as potential drugs targets. Our integrative network-based system-level approach would help to find the genetic variants of OC that can accelerate drug discovery outcomes to develop a better understanding regarding treatment strategies for many cancer types.
The value of intra-operative electrographic biomarkers for tailoring during epilepsy surgery: from group-level to patient-level analysis
Authors: Demuru Matteo , Kalitzin Stiliyan , Zweiphenning Willemiek , van Blooijs Dorien , van’t Klooster Maryse , Van Eijsden Pieter , Leijten Frans , Zijlmans Maeike ,   RESPect Group, Braun Kees , Ferrier Cyrille , Gebbink Tineke , Gosselaar Peter , Huiskamp Geertjan , van Klink Nicole , Ophorst Janine , van Rijen Peter , van der Salm Sandra , Winter Anouk Velders-de 
Published: September 2020

AbstractSignal analysis biomarkers, in an intra-operative setting, may be complementary tools to guide and tailor the resection in drug-resistant focal epilepsy patients. Effective assessment of biomarker performances are needed to evaluate their clinical usefulness and translation. We defined a realistic ground-truth scenario and compared the effectiveness of different biomarkers alone and combined to localize epileptogenic tissue during surgery. We investigated the performances of univariate, bivariate and multivariate signal biomarkers applied to 1 min inter-ictal intra-operative electrocorticography to discriminate between epileptogenic and non-epileptogenic locations in 47 drug-resistant people with epilepsy (temporal and extra-temporal) who had been seizure-free one year after the operation. The best result using a single biomarker was obtained using the phase-amplitude coupling measure for which the epileptogenic tissue was localized in 17 out of 47 patients. Combining the whole set of biomarkers provided an improvement of the performances: 27 out of 47 patients. Repeating the analysis only on the temporal-lobe resections we detected the epileptogenic tissue in 29 out of 30 combining all the biomarkers. We suggest that the assessment of biomarker performances on a ground-truth scenario is required to have a proper estimate on how biomarkers translate into clinical use. Phase-amplitude coupling seems the best performing single biomarker and combining biomarkers improves localization of epileptogenic tissue. Performance achieved is not adequate as a tool in the operation theater yet, but it can improve the understanding of pathophysiological process.
Genome sequence of segmented filamentous bacteria present in the human intestine
Authors: Jonsson Hans , Hugerth Luisa W. , Sundh John , Lundin Eva , Andersson Anders F. 
Published: September 2020

AbstractSegmented filamentous bacteria (SFB) are unique immune modulatory bacteria colonizing the small intestine of a variety of animals in a host-specific manner. SFB exhibit filamentous growth and attach to the host’s intestinal epithelium, offering a physical route of interaction. SFB affect functions of the host immune system, among them IgA production and T-cell maturation. Until now, no human-specific SFB genome has been reported. Here, we report the metagenomic reconstruction of an SFB genome from a human ileostomy sample. Phylogenomic analysis clusters the genome with SFB genomes from mouse, rat and turkey, but the genome is genetically distinct, displaying 65–71% average amino acid identity to the others. By screening human faecal metagenomic datasets, we identified individuals carrying sequences identical to the new SFB genome. We thus conclude that a unique SFB variant exists in humans and foresee a renewed interest in the elucidation of SFB functionality in this environment.
Apple latent spherical virus structure with stable capsid frame supports quasi-stable protrusions expediting genome release
Authors: Naitow Hisashi , Hamaguchi Tasuku , Maki-Yonekura Saori , Isogai Masamichi , Yoshikawa Nobuyuki , Yonekura Koji 
Published: September 2020

AbstractPicorna-like plant viruses are non-enveloped RNA spherical viruses of ~30 nm. Part of the survival of these viruses depends on their capsid being stable enough to harbour the viral genome and yet malleable enough to allow its release. However, molecular mechanisms remain obscure. Here, we report a structure of a picorna-like plant virus, apple latent spherical virus, at 2.87 Å resolution by single-particle cryo-electron microscopy (cryo-EM) with a cold-field emission beam. The cryo-EM map reveals a unique structure composed of three capsid proteins Vp25, Vp20, and Vp24. Strikingly Vp25 has a long N-terminal extension, which substantially stabilises the capsid frame of Vp25 and Vp20 subunits. Cryo-EM images also resolve RNA genome leaking from a pentameric protrusion of Vp24 subunits. The structures and observations suggest that genome release occurs through occasional opening of the Vp24 subunits, possibly suppressed to a low frequency by the rigid frame of the other subunits.
Nanobenders as efficient piezoelectric actuators for widely tunable nanophotonics at CMOS-level voltages
Authors: Jiang Wentao , Mayor Felix M. , Patel Rishi N. , McKenna Timothy P. , Sarabalis Christopher J. , Safavi-Naeini Amir H. 
Published: September 2020

AbstractTuning and reconfiguring of nanophotonic components are needed to realize systems incorporating many components. The electrostatic force can deform a structure and tune its optical response. Despite the success of electrostatic actuators, they suffer from trade-offs between tuning voltage, tuning range, and on-chip area. Piezoelectric actuation could resolve these challenges, but only pm-per-volt scale wavelength tunability has been achieved. Here we propose and demonstrate compact piezoelectric actuators, called nanobenders, that transduce tens of nanometers per volt. By leveraging the non-uniform electric field from submicron electrodes, we generate bending of a piezoelectric nanobeam. Combined with a sliced photonic crystal cavity to sense displacement, we show tuning of an optical resonance by ~ 5 nm V−1 (0.6 THz V−1) and between 1520 ~ 1560 nm (~ 400 linewidths) within 4 V. Finally, we consider tunable nanophotonic components enabled by the nanobenders.