bluuebunny/crossref_metadata_2025 huggingface dataset:
Cellular origins and genetic landscape of cutaneous gamma delta T cell lymphomas
Authors: Daniels Jay , Doukas Peter G. , Escala Maria E. Martinez , Ringbloom Kimberly G. , Shih David J. H. , Yang Jingyi , Tegtmeyer Kyle , Park Joonhee , Thomas Jane J. , Selli Mehmet E. , Altunbulakli Can , Gowthaman Ragul , Mo Samuel H. , Jothishankar Balaji , Pease David R. , Pro Barbara , Abdulla Farah R. , Shea Christopher , Sahni Nidhi , Gru Alejandro A. , Pierce Brian G. , Louissaint Abner , Guitart Joan , Choi Jaehyuk
Published: April 2020

Primary cutaneous γδ T cell lymphomas (PCGDTLs) represent a heterogeneous group of uncommon but aggressive cancers. Herein, we perform genome-wide DNA, RNA, and T cell receptor (TCR) sequencing on 29 cutaneous γδ lymphomas. We find that PCGDTLs are not uniformly derived from Vδ2 cells. Instead, the cell-of-origin depends on the tissue compartment from which the lymphomas are derived. Lymphomas arising from the outer layer of skin are derived from Vδ1 cells, the predominant γδ cell in the epidermis and dermis. In contrast, panniculitic lymphomas arise from Vδ2 cells, the predominant γδ T cell in the fat. We also show that TCR chain usage is non-random, suggesting common antigens for Vδ1 and Vδ2 lymphomas respectively. In addition, Vδ1 and Vδ2 PCGDTLs harbor similar genomic landscapes with potentially targetable oncogenic mutations in the JAK/STAT, MAPK, MYC, and chromatin modification pathways. Collectively, these findings suggest a paradigm for classifying, staging, and treating these diseases.
Selective inhibition of cancer cell self-renewal through a Quisinostat-histone H1.0 axis
Authors: Morales Torres Cristina , Wu Mary Y. , Hobor Sebastijan , Wainwright Elanor N. , Martin Matthew J. , Patel Harshil , Grey William , Grönroos Eva , Howell Steven , Carvalho Joana , Snijders Ambrosius P. , Bustin Michael , Bonnet Dominique , Smith Paul D. , Swanton Charles , Howell Michael , Scaffidi Paola
Published: April 2020

Continuous cancer growth is driven by subsets of self-renewing malignant cells. Targeting of uncontrolled self-renewal through inhibition of stem cell-related signaling pathways has proven challenging. Here, we show that cancer cells can be selectively deprived of self-renewal ability by interfering with their epigenetic state. Re-expression of histone H1.0, a tumor-suppressive factor that inhibits cancer cell self-renewal in many cancer types, can be broadly induced by the clinically well-tolerated compound Quisinostat. Through H1.0, Quisinostat inhibits cancer cell self-renewal and halts tumor maintenance without affecting normal stem cell function. Quisinostat also hinders expansion of cells surviving targeted therapy, independently of the cancer types and the resistance mechanism, and inhibits disease relapse in mouse models of lung cancer. Our results identify H1.0 as a major mediator of Quisinostat’s antitumor effect and suggest that sequential administration of targeted therapy and Quisinostat may be a broadly applicable strategy to induce a prolonged response in patients.
Chronic activation of hexosamine biosynthesis in the heart triggers pathological cardiac remodeling
Authors: Tran Diem Hong , May Herman I. , Li Qinfeng , Luo Xiang , Huang Jian , Zhang Guangyu , Niewold Erica , Wang Xiaoding , Gillette Thomas G. , Deng Yingfeng , Wang Zhao V.
Published: April 2020

The hexosamine biosynthetic pathway (HBP) plays critical roles in nutrient sensing, stress response, and cell growth. However, its contribution to cardiac hypertrophic growth and heart failure remains incompletely understood. Here, we show that the HBP is induced in cardiomyocytes during hypertrophic growth. Overexpression of Gfat1 (glutamine:fructose-6-phosphate amidotransferase 1), the rate-limiting enzyme of HBP, promotes cardiomyocyte growth. On the other hand, Gfat1 inhibition significantly blunts phenylephrine-induced hypertrophic growth in cultured cardiomyocytes. Moreover, cardiac-specific overexpression of Gfat1 exacerbates pressure overload-induced cardiac hypertrophy, fibrosis, and cardiac dysfunction. Conversely, deletion of Gfat1 in cardiomyocytes attenuates pathological cardiac remodeling in response to pressure overload. Mechanistically, persistent upregulation of the HBP triggers decompensated hypertrophy through activation of mTOR while Gfat1 deficiency shows cardioprotection and a concomitant decrease in mTOR activity. Taken together, our results reveal that chronic upregulation of the HBP under hemodynamic stress induces pathological cardiac hypertrophy and heart failure through persistent activation of mTOR.
An in vivo platform to select and evolve aggregation-resistant proteins
Authors: Ebo Jessica S. , Saunders Janet C. , Devine Paul W. A. , Gordon Alice M. , Warwick Amy S. , Schiffrin Bob , Chin Stacey E. , England Elizabeth , Button James D. , Lloyd Christopher , Bond Nicholas J. , Ashcroft Alison E. , Radford Sheena E. , Lowe David C. , Brockwell David J.
Published: April 2020

Protein biopharmaceuticals are highly successful, but their utility is compromised by their propensity to aggregate during manufacture and storage. As aggregation can be triggered by non-native states, whose population is not necessarily related to thermodynamic stability, prediction of poorly-behaving biologics is difficult, and searching for sequences with desired properties is labour-intensive and time-consuming. Here we show that an assay in the periplasm of E. coli linking aggregation directly to antibiotic resistance acts as a sensor for the innate (un-accelerated) aggregation of antibody fragments. Using this assay as a directed evolution screen, we demonstrate the generation of aggregation resistant scFv sequences when reformatted as IgGs. This powerful tool can thus screen and evolve ‘manufacturable’ biopharmaceuticals early in industrial development. By comparing the mutational profiles of three different immunoglobulin scaffolds, we show the applicability of this method to investigate protein aggregation mechanisms important to both industrial manufacture and amyloid disease.
Computational analysis of pathological images enables a better diagnosis of TFE3 Xp11.2 translocation renal cell carcinoma
Authors: Cheng Jun , Han Zhi , Mehra Rohit , Shao Wei , Cheng Michael , Feng Qianjin , Ni Dong , Huang Kun , Cheng Liang , Zhang Jie
Published: April 2020

TFE3 Xp11.2 translocation renal cell carcinoma (TFE3-RCC) generally progresses more aggressively compared with other RCC subtypes, but it is challenging to diagnose TFE3-RCC by traditional visual inspection of pathological images. In this study, we collect hematoxylin and eosin- stained histopathology whole-slide images of 74 TFE3-RCC cases (the largest cohort to date) and 74 clear cell RCC cases (ccRCC, the most common RCC subtype) with matched gender and tumor grade. An automatic computational pipeline is implemented to extract image features. Comparative study identifies 52 image features with significant differences between TFE3-RCC and ccRCC. Machine learning models are built to distinguish TFE3-RCC from ccRCC. Tests of the classification models on an external validation set reveal high accuracy with areas under ROC curve ranging from 0.842 to 0.894. Our results suggest that automatically derived image features can capture subtle morphological differences between TFE3-RCC and ccRCC and contribute to a potential guideline for TFE3-RCC diagnosis.
Proper chromosome alignment depends on BRCA2 phosphorylation by PLK1
Authors: Ehlén Åsa , Martin Charlotte , Miron Simona , Julien Manon , Theillet François-Xavier , Ropars Virginie , Sessa Gaetana , Beaurepere Romane , Boucherit Virginie , Duchambon Patricia , El Marjou Ahmed , Zinn-Justin Sophie , Carreira Aura
Published: April 2020

The BRCA2 tumor suppressor protein is involved in the maintenance of genome integrity through its role in homologous recombination. In mitosis, BRCA2 is phosphorylated by Polo-like kinase 1 (PLK1). Here we describe how this phosphorylation contributes to the control of mitosis. We identify a conserved phosphorylation site at T207 of BRCA2 that constitutes a bona fide docking site for PLK1 and is phosphorylated in mitotic cells. We show that BRCA2 bound to PLK1 forms a complex with the phosphatase PP2A and phosphorylated-BUBR1. Reducing BRCA2 binding to PLK1, as observed in BRCA2 breast cancer variants S206C and T207A, alters the tetrameric complex resulting in unstable kinetochore-microtubule interactions, misaligned chromosomes, faulty chromosome segregation and aneuploidy. We thus reveal a role of BRCA2 in the alignment of chromosomes, distinct from its DNA repair function, with important consequences on chromosome stability. These findings may explain in part the aneuploidy observed in BRCA2-mutated tumors.
Observation of quadratic Weyl points and double-helicoid arcs
Authors: He Hailong , Qiu Chunyin , Cai Xiangxi , Xiao Meng , Ke Manzhu , Zhang Fan , Liu Zhengyou
Published: April 2020

Novel quasiparticles beyond those mimicking the elementary high-energy particles such as Dirac and Weyl fermions have attracted great interest in condensed-matter physics and materials science. Here we report an experimental observation of the long-desired quadratic Weyl points by using a three-dimensional chiral metacrystal of sound waves. Markedly different from the newly observed unconventional quasiparticles, such as the spin-1 Weyl points and the charge-2 Dirac points featuring respectively threefold and fourfold band crossings, the charge-2 Weyl points identified here are simply twofold degenerate, and the dispersions around them are quadratic in two directions and linear in the third one. Besides the essential nonlinear bulk dispersions, we further unveil the exotic double-helicoid surface arcs that emanate from a projected quadratic Weyl point and terminate at two projected conventional Weyl points. This unique global surface connectivity provides conclusive evidence for the double topological charges of such unconventional topological nodes.
Nonlinear rheological characteristics of single species bacterial biofilms
Authors: Jana Saikat , Charlton Samuel G. V. , Eland Lucy E. , Burgess J. Grant , Wipat Anil , Curtis Thomas P. , Chen Jinju
Published: April 2020

Bacterial biofilms in natural and artificial environments perform a wide array of beneficial or detrimental functions and exhibit resistance to physical as well as chemical perturbations. In dynamic environments, where periodic or aperiodic flows over surfaces are involved, biofilms can be subjected to large shear forces. The ability to withstand these forces, which is often attributed to the resilience of the extracellular matrix. This attribute of the extracellular matrix is referred to as viscoelasticity and is a result of self-assembly and cross-linking of multiple polymeric components that are secreted by the microbes. We aim to understand the viscoelastic characteristic of biofilms subjected to large shear forces by performing Large Amplitude Oscillatory Shear (LAOS) experiments on four species of bacterial biofilms: Bacillus subtilis, Comamonas denitrificans, Pseudomonas fluorescens and Pseudomonas aeruginosa. We find that nonlinear viscoelastic measures such as intracycle strain stiffening and intracycle shear thickening for each of the tested species, exhibit subtle or distinct differences in the plot of strain amplitude versus frequency (Pipkin diagram). The biofilms also exhibit variability in the onset of nonlinear behaviour and energy dissipation characteristics, which could be a result of heterogeneity of the extracellular matrix constituents of the different biofilms. The results provide insight into the nonlinear rheological behaviour of biofilms as they are subjected to large strains or strain rates; a situation that is commonly encountered in nature, but rarely investigated.
Theoretical investigation of a potentially important formation pathway of organosulfate in atmospheric aqueous aerosols
Authors: Chen Kunpeng , Zhao Jun
Published: April 2020

Organic sulfate plays important roles in modulating properties of atmospheric aerosols. Recent studies showed that organic sulfate was likably interpreted as inorganic sulfate in field measurements using advanced instruments such as Aerosol Mass Spectrometer and the major contributor to organic sulfate was thought to be hydroxymethanesulfonate (HMS). This study proposed that besides HMS, its isomer hydroxymethyl sulfite (HMSi), which has not been identified in atmospheric aerosols, can emerge as the product of aqueous reactions between sulfur dioxide and formaldehyde. Results from quantum chemical modeling showed that formation of HMS and HMSi was several orders of magnitude faster than that of their corresponding conjugate acids, HMSA and HMHSi. In addition, water involvement can largely accelerate respectively the formation rate of HMS/HMSA and HMSi, but decelerate that of HMHSi, demonstrating the non-negligible role of water in the formation process. Furthermore, our kinetic model implemented with the calculated parameters indicates that HMSi/HMHSi but not HMS/HMSA can significantly alter the pH values of atmospheric aqueous aerosols and HMHSi is the most abundant species among HMS/HMSA and HMSi/HMHSi. Therefore, the newly-discovered pathway via HMSi/HMHSi formation should be of great concern and its kinetic parameters should be implemented in future models of atmospheric chemistry.
Receptor-interacting serine/threonine kinase 1- and 3-dependent inflammation induced in lungs of chicken infected with Pasteurella multocida
Authors: Li Weitian , Tang Qiyu , Dai Na , Feng Weikuan , Xie Changqing , Cheng Guofu , Liu Xiaoli , Zhang Wanpo , Hu Xueying , Gu Changqin
Published: April 2020

Fowl cholera is a serious, highly contagious disease caused by the bacterium Pasteurella multocida (P. multocida) in a range of avian species and is characterized by an acute form of septicaemia. The pathogenic mechanism of chicken lung injury caused by the bacterium is unclear. Therefore, P. multocida Q (a reference standard strain isolated from chicken) and 1G1 (a clinic isolated strain from duck) were selected to infect chickens, establishing fowl cholera-induced laying hen models. Several important proteins involved in the process of lung injury were identified and quantified using immunohistochemistry and WB. The results showed that chicken lungs infected with bacteria for 24 h showed congestion and edema. The inflammatory factors HMGB1 and IL-6, intercellular matrix MMP, the cell apoptosis-associated caspase-3 and necrotic apoptosis signal molecules RIPK1 and RIPK3 were widely expressed in the lungs of group Q and were significantly different compared with those of 1G1 group and uninfected group (P < 0.05). The results indicated that RIPK1 and RIPK3 are involved in the injury process of chicken lungs after infection with P. multocida, and the mechanisms of lung injury induced by different strains are different.
Predictive Analytics for Retention in Care in an Urban HIV Clinic
Authors: Ramachandran Arthi , Kumar Avishek , Koenig Hannes , De Unanue Adolfo , Sung Christina , Walsh Joe , Schneider John , Ghani Rayid , Ridgway Jessica P.
Published: April 2020

Consistent medical care among people living with HIV is essential for both individual and public health. HIV-positive individuals who are ‘retained in care’ are more likely to be prescribed antiretroviral medication and achieve HIV viral suppression, effectively eliminating the risk of transmitting HIV to others. However, in the United States, less than half of HIV-positive individuals are retained in care. Interventions to improve retention in care are resource intensive, and there is currently no systematic way to identify patients at risk for falling out of care who would benefit from these interventions. We developed a machine learning model to identify patients at risk for dropping out of care in an urban HIV care clinic using electronic medical records and geospatial data. The machine learning model has a mean positive predictive value of 34.6% [SD: 0.15] for flagging the top 10% highest risk patients as needing interventions, performing better than the previous state-of-the-art logistic regression model (PPV of 17% [SD: 0.06]) and the baseline rate of 11.1% [SD: 0.02]. Machine learning methods can improve the prediction ability in HIV care clinics to proactively identify patients at risk for not returning to medical care.
RNA-Seq of human whole blood: Evaluation of globin RNA depletion on Ribo-Zero library method
Authors: Harrington Christina A. , Fei Suzanne S. , Minnier Jessica , Carbone Lucia , Searles Robert , Davis Brett A. , Ogle Kimberly , Planck Stephen R. , Rosenbaum James T. , Choi Dongseok
Published: April 2020

Peripheral blood is a highly accessible biofluid providing a rich source of information about human physiology and health status. However, for studies of the blood transcriptome with RNA sequencing (RNA-Seq) techniques, high levels of hemoglobin mRNAs (hgbRNA) present in blood can occupy valuable sequencing space, impacting detection and quantification of non-hgbRNAs. In this study, we evaluated two methods for preparing ribosomal RNA (rRNA)-depleted sequencing libraries for RNA-Seq of whole blood, one of which is also designed to deplete hgbRNAs. Two experiments were performed: one evaluating library performance across 6 human blood samples and the other examining library reproducibility and performance in a two-subject subset. We find that addition of hgbRNA depletion to the rRNA-depletion protocol for library preparation from blood RNA effectively reduces highly abundant hgbRNA reads; however, it does not result in a statistically significant increase in differentially expressed genes in our patient-control study. Bioinformatic removal of globin gene counts in non-hgbRNA depleted libraries provides improvement in overall performance of these libraries. We conclude that use of a standard ribosomal RNA depletion method for library preparation coupled with bioinformatic removal of globin gene counts is sufficient for reproducible and sensitive measurement of both coding and noncoding RNAs in the blood transcriptome.
Novel insight into theacrine metabolism revealed by transcriptome analysis in bitter tea (Kucha, Camellia sinensis)
Authors: Wang Songlin , Chen Jiedan , Ma Jianqiang , Jin Jiqiang , Chen Liang , Yao Mingzhe
Published: April 2020

Kucha (Camellia sinensis) is a kind of unique wild tea resources in southwest China, containing sizeable amounts of theacrine (1,3,7,9-tetramethyluric acid) and having a special bitter taste both in fresh leaves and made tea. Theacrine has good healthy function locally. But the molecular mechanism of theacrine metabolism in Kucha was still unclear. In order to illuminate the biosynthesis and catabolism of theacrine in Kucha plants, three tea cultivars, C. sinensis ‘Shangyou Zhongye’ (SY) with low-theacrine, ‘Niedu Kucha 2’ (ND2) with middle-theacrine and, ‘Niedu Kucha 3’ (ND3) with high-theacrine, were used for our research. Purine alkaloid analysis and transcriptome of those samples were performed by High Performance Liquid Chromatography (HPLC) and RNA-Seq, respectively. The related gene expression levels of purine alkaloid were correlated with the content of purine alkaloid, and the results of quantitative real-time (qRT) PCR were also confirmed the reliability of transcriptome. Based on the data, we found that theacrine biosynthesis is a relatively complex process, N-methyltransferase (NMT) encoded by TEA024443 may catalyze the methylation at 9-N position in Kucha plant. Our finding will assist to reveal the molecular mechanism of theacrine biosynthesis, and be applied to selection and breeding of Kucha tea cultivars in the future.
Enhanced myostatin expression and signalling promote tubulointerstitial inflammation in diabetic nephropathy
Authors: Verzola Daniela , Milanesi Samantha , Viazzi Francesca , Ansaldo Francesca , Saio Michela , Garibaldi Silvano , Carta Annalisa , Costigliolo Francesca , Salvidio Gennaro , Barisione Chiara , Esposito Pasquale , Garibotto Giacomo , Picciotto Daniela
Published: April 2020

Myostatin (MSTN), a family member of the transforming growth factor (TGF)-β super family, has been detected in the tubuli of pig kidney, but its role in the human kidney is not known. In this study we observed upregulation of MSTN mRNA (~8 to 10-fold increase) both in the glomeruli and tubulointerstitium in diabetic nephropathy (DN). In DN, immunoreactive MSTN was mainly localized in the tubuli and interstitium (∼4–8 fold increase), where it colocalized in CD45+ cells. MSTN was also upregulated in the glomeruli and the arterial vessels. Tubulointerstitial MSTN expression was directly related to interstitial fibrosis (r = 0.54, p < 0.01). In HK-2 tubular epithelial cells, both high (30 mmol) glucose and glycated albumin upregulated MSTN mRNA and its protein (p < 0.05–0.01). MSTN-treated HK-2 cells underwent decreased proliferation, together with NF-kB activation and CCL-2 and SMAD 2,3 overexpression. In addition, MSTN induced intracellular ROS release and upregulated NADPH oxidase, effects which were mediated by ERK activation. In conclusion, our data show that MSTN is expressed in the human kidney and overexpressed in DN, mainly in the tubulointerstitial compartment. Our results also show that MSTN is a strong inducer of proximal tubule activation and suggest that MSTN overexpression contributes to kidney interstitial fibrosis in DN.
Habitual use of GPS negatively impacts spatial memory during self-guided navigation
Authors: Dahmani Louisa , Bohbot Véronique D.
Published: April 2020

Global Positioning System (GPS) navigation devices and applications have become ubiquitous over the last decade. However, it is unclear whether using GPS affects our own internal navigation system, or spatial memory, which critically relies on the hippocampus. We assessed the lifetime GPS experience of 50 regular drivers as well as various facets of spatial memory, including spatial memory strategy use, cognitive mapping, and landmark encoding using virtual navigation tasks. We first present cross-sectional results that show that people with greater lifetime GPS experience have worse spatial memory during self-guided navigation, i.e. when they are required to navigate without GPS. In a follow-up session, 13 participants were retested three years after initial testing. Although the longitudinal sample was small, we observed an important effect of GPS use over time, whereby greater GPS use since initial testing was associated with a steeper decline in hippocampal-dependent spatial memory. Importantly, we found that those who used GPS more did not do so because they felt they had a poor sense of direction, suggesting that extensive GPS use led to a decline in spatial memory rather than the other way around. These findings are significant in the context of society’s increasing reliance on GPS.
Alkyl-carbon chain length of two distinct compounds and derivatives are key determinants of their anti-Acanthamoeba activities
Authors: Mooney Ronnie , Masala Mariana , Martial Theo , McGinness Charles , Henriquez Fiona Luisa , Williams Roderick Adeyinka Malcolm
Published: April 2020

The opportunistic pathogen, Acanthamoeba castellanii is the causative agent for the sight threatening infection Acanthamoeba keratitis (AK). It is commonly associated with contact lens wearers, and prevalence is increasing at an alarming rate due to an inadequate preventive strategy to protect the lens from this protist. This problem is compounded by the lack of an effective acanthamoebocide, particularly with cysticidal activity in the contact lens solutions. We have used cytotoxicity assays and a variety of biophysical approaches to show that two molecules with tails made of alkyl carbon, alkylphosphocholines (APCs) and quaternary ammonium compounds (QACs) had significant chain-length dependent efficacy against A. castellanii trophozoites, the latter producing death via permeabilization, and DNA complexing. QACs were more effective than APCs and had activity against cysts. Conversely, the QAC with 12 alkyl carbon chain, was non toxic, its presence increased A. castellanii trophozoites biomass and delayed encystation by 96 h. Interestingly, it was unable to induce excystation and increased trophozoite sensitivity to APC16. These results present a mono- and multi-inhibitor management strategy effective against trophozoites and cysts that may be useful for formulating into contact lense cleaning solutions and reducing AK incidence.
Soyasapogenol-A targets CARF and results in suppression of tumor growth and metastasis in p53 compromised cancer cells
Authors: Omar Amr , Kalra Rajkumar Singh , Putri Jayarani , Elwakeel Ahmed , Kaul Sunil C. , Wadhwa Renu
Published: April 2020

We screened some phytochemicals for cytotoxic activity to human cancer cells and identified Soyasapogenol-A (Snol-A) as a potent candidate anti-cancer compound. Interestingly, Soyasapogenin-I (Snin-I) was ineffective. Viability assays endorsed toxicity of Snol-A to a wide variety of cancer cells. Of note, wild type p53 deficient cancer cells (SKOV-3 and Saos-2) also showed potent growth inhibitory effect. Molecular analyses demonstrated that it targets CARF yielding transcriptional upregulation of p21WAF1 (an inhibitor of cyclin-dependent kinases) and downregulation of its effector proteins, CDK2, CDK-4, Cyclin A and Cyclin D1. Targeting of CARF by Snol-A also caused (i) downregulation of pATR-Chk1 signaling leading to caspase-mediated apoptosis and (ii) inactivation of β-catenin/Vimentin/hnRNPK-mediated EMT signaling resulting in decrease in migration and invasion of cancer cells. In in vivo assays, Snol-A caused suppression of tumor growth in subcutaneous xenograft model and inhibited lung metastasis in tail vein injection model. Taken together, we demonstrate that Snol-A is a natural inhibitor of CARF and may be recruited as a potent anti-tumor and anti-metastasis compound for treatment of p53-deficient aggressive malignancies.
The feasibility of differentiating colorectal cancer from normal and inflammatory thickening colon wall using CT texture analysis
Authors: Wang Xiao , Yuan Mingyuan , Mi Honglan , Suo Shiteng , Eteer Khalid , Li Suqin , Lu Qing , Xu Jianrong , Hu Jiani
Published: April 2020

To investigate the diagnostic value of texture analysis (TA) for differentiating between colorectal cancer (CRC), colonic lesions caused by inflammatory bowel disease (IBD), and normal thickened colon wall (NTC) on computed tomography (CT) and assess which scanning phase has the highest differential diagnostic value. In all, 107 patients with CRC, 113 IBD patients with colonic lesions, and 96 participants with NTC were retrospectively enrolled. All subjects underwent multiphase CT examination, including pre-contrast phase (PCP), arterial phase (AP), and portal venous phase (PVP) scans. Based on these images, classification by TA and visual classification by radiologists were performed to discriminate among the three tissue types. The performance of TA and visual classification was compared. Precise TA classification results (error, 2.03–12.48%) were acquired by nonlinear discriminant analysis for CRC, IBD and NTC, regardless of phase or feature selection. PVP images showed a better ability to discriminate the three tissues by comprising the three scanning phases. TA showed significantly better performance in discriminating CRC, IBD and NTC than visual classification for residents, but there was no significant difference in classification between TA and experienced radiologists. TA could provide useful quantitative information for the differentiation of CRC, IBD and NTC on CT, particularly in PVP images.
Comparison of auditory spatial bisection and minimum audible angle in front, lateral, and back space
Authors: Aggius-Vella Elena , Kolarik Andrew J. , Gori Monica , Cirstea Silvia , Campus Claudio , Moore Brian C. J. , Pardhan Shahina
Published: April 2020

Although vision is important for calibrating auditory spatial perception, it only provides information about frontal sound sources. Previous studies of blind and sighted people support the idea that azimuthal spatial bisection in frontal space requires visual calibration, while detection of a change in azimuth (minimum audible angle, MAA) does not. The influence of vision on the ability to map frontal, lateral and back space has not been investigated. Performance in spatial bisection and MAA tasks was assessed for normally sighted blindfolded subjects using bursts of white noise presented frontally, laterally, or from the back relative to the subjects. Thresholds for both tasks were similar in frontal space, lower for the MAA task than for the bisection task in back space, and higher for the MAA task in lateral space. Two interpretations of the results are discussed, one in terms of visual calibration and the use of internal representations of source location and the other based on comparison of the magnitude or direction of change of the available binaural cues. That bisection thresholds were increased in back space relative to front space, where visual calibration information is unavailable, suggests that an internal representation of source location was used for the bisection task.
A three-dimensional bioprinted model to evaluate the effect of stiffness on neuroblastoma cell cluster dynamics and behavior
Authors: Monferrer Ezequiel , Martín-Vañó Susana , Carretero Aitor , García-Lizarribar Andrea , Burgos-Panadero Rebeca , Navarro Samuel , Samitier Josep , Noguera Rosa
Published: April 2020

Three-dimensional (3D) bioprinted culture systems allow to accurately control microenvironment components and analyze their effects at cellular and tissue levels. The main objective of this study was to identify, quantify and localize the effects of physical-chemical communication signals between tumor cells and the surrounding biomaterial stiffness over time, defining how aggressiveness increases in SK-N-BE(2) neuroblastoma (NB) cell line. Biomimetic hydrogels with SK-N-BE(2) cells, methacrylated gelatin and increasing concentrations of methacrylated alginate (AlgMA 0%, 1% and 2%) were used. Young’s modulus was used to define the stiffness of bioprinted hydrogels and NB tumors. Stained sections of paraffin-embedded hydrogels were digitally quantified. Human NB and 1% AlgMA hydrogels presented similar Young´s modulus mean, and orthotopic NB mice tumors were equally similar to 0% and 1% AlgMA hydrogels. Porosity increased over time; cell cluster density decreased over time and with stiffness, and cell cluster occupancy generally increased with time and decreased with stiffness. In addition, cell proliferation, mRNA metabolism and antiapoptotic activity advanced over time and with stiffness. Together, this rheological, optical and digital data show the potential of the 3Din vitrocell model described herein to infer how intercellular space stiffness patterns drive the clinical behavior associated with NB patients.
Systemic and pulmonary C1q as biomarker of progressive disease in experimental non-human primate tuberculosis
Authors: Dijkman Karin , Lubbers Rosalie , Borggreven Nicole V. , Ottenhoff Tom H. M. , Joosten Simone A. , Trouw Leendert A. , Verreck Frank A. W.
Published: April 2020

Tuberculosis (TB) causes 1.6 million deaths annually. Early differential diagnosis of active TB infection is essential in optimizing treatment and reducing TB mortality, but is hampered by a lack of accurate and accessible diagnostics. Previously, we reported on complement component C1q, measured in serum by ELISA, as a candidate biomarker for active tuberculosis. In this work we further examine the dynamics of C1q as a marker of progressive TB disease in non-human primates (NHP). We assessed systemic and pulmonary C1q levels after experimental infection using high or low single dose as well as repeated limiting dose Mycobacterium tuberculosis (Mtb) challenge of macaques. We show that increasing C1q levels, either peripherally or locally, correlate with progressive TB disease, assessed by PET-CT imaging or post-mortem evaluation. Upregulation of C1q did not precede detection of Mtb infection by a conventional interferon-gamma release assay, confirming its association with disease progression. Finally, pulmonary vaccination with Bacillus Calmette Guérin also increased local production of C1q, which might contribute to the generation of pulmonary protective immunity. Our data demonstrate that NHP modelling of TB can be utilized to study the role of C1q as a liquid biomarker in TB protection and disease, complementing findings in TB patients.
Co-actors Exhibit Similarity in Their Structure of Behavioural Variation That Remains Stable Across Range of Naturalistic Activities
Authors: Rigoli Lillian M. , Lorenz Tamara , Coey Charles , Kallen Rachel , Jordan Scott , Richardson Michael J.
Published: April 2020

Human behaviour, along with any natural/biological behaviour, has varying degrees of intrinsic ‘noise’ or variability. Many studies have shown that the structure or patterning of this variability is sensitive to changes in task and constraint. Furthermore, two or more humans interacting together often begin to exhibit similar structures of behavioural variability (i.e., the patterning of their behavioural fluctuations becomes aligned or matched) independent of any moment-to-moment synchronization (termed complexity matching). However, much of the previous work has focused on a subset of simple or contrived behaviours within the context of highly controlled laboratory tasks. In the current study, individuals and pairs performed five self-paced (unsupervised), semi-structured activities around a university campus. Empatica E4 wristbands and iPhones were used to record the participants’ behavioural activity via accelerometers and GPS. The results revealed that the structure of variability in naturalistic human behaviour co-varies with the task-goal constraints, and that the patterning of the behavioural fluctuations exhibited by co-acting individuals does become aligned during the performance of everyday activities. The results also revealed that the degree of complexity matching that occurred between pairs remained invariant across activity type, indicating that this measure could be employed as a robust, task-independent index of interpersonal behaviour.
Evaluation of computer aided detection of tuberculosis on chest radiography among people with diabetes in Karachi Pakistan
Authors: Habib Shifa Salman , Rafiq Sana , Zaidi Syed Mohammad Asad , Ferrand Rashida Abbas , Creswell Jacob , Van Ginneken Bram , Jamal Wafa Zehra , Azeemi Kiran Sohail , Khowaja Saira , Khan Aamir
Published: April 2020

Pakistan ranks fifth among high tuberculosis (TB) burden countries and also has seventh highest burden for diabetes mellitus (DM). DM increases the risk of developing TB and contributes to adverse TB treatment outcomes hence screening and integrated management for both diseases in high burden countries is suggested. Computer-Aided Detection for TB (CAD4TB) can potentially be used as triage tool in low resource settings to pre-screen individuals for Xpert MTB/RIF testing. The aim of this study was to evaluate the diagnostic accuracy and performance of CAD4TB software in people with diabetes (PWD) enrolled in a TB screening program in Karachi, Pakistan. A total of 694 individuals with a diagnosis of DM (of whom 31.1% were newly diagnosed) were screened with CAD4TB and simultaneously provided sputum for Xpert MTB/RIF testing. Of the 74 (10.7%) participants who had bacteriologically positive (MTB+) results on Xpert testing, 54 (73%) had a CAD4TB score >70; and 155 (25%) participants who tested MTB-negative had scores >70. The area under the receiver operator curve was 0.78 (95% CI: 0.77–0.80). Our study findings indicate that CAD4TB offers good diagnostic accuracy as a triage test for TB screening among PWD using Xpert MTB/RIF as the reference standard.
Publisher Correction: Inadequate Folic Acid Intake Among Women Taking Antiepileptic Drugs During Pregnancy in Japan: A Cross-Sectional Study
Authors: Ikeda-Sakai Yasuko , Saito Yoshiyuki , Obara Taku , Goto Mikako , Sengoku Tami , Takahashi Yoshimitsu , Hamada Hiromi , Nakayama Takeo , Murashima Atsuko
Published: April 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Polyoxometalate chemistry at volcanoes: discovery of a novel class of polyoxocuprate nanoclusters in fumarolic minerals
Authors: Britvin S. N. , Pekov I. V. , Yapaskurt V. O. , Koshlyakova N. N. , Göttlicher J. , Krivovichev S. V. , Turchkova A. G. , Sidorov E. G.
Published: April 2020

Polyoxometalate (POM) chemistry is an important avenue of comprehensive chemical research, due to the broad chemical, topological and structural variations of multinuclear polyoxoanions that result in advanced functionality of their derivatives. The majority of compounds in the polyoxometalate kingdom are synthesized under laboratory conditions. However, Nature has its own labs with the conditions often unconceivable to the mankind. The striking example of such a unique environment is volcanic fumaroles – the natural factories of gas-transport synthesis. We herein report on the discovery of a novel class of complex polyoxocuprates grown in the hot active fumaroles of the Tolbachik volcano at the Kamchatka Peninsula, Russia. The cuboctahedral nanoclusters {[MCu12O8](AsO4)8} are stabilized by the core Fe(III) or Ti(IV) cations residing in the unique cubic coordination. The nanoclusters are uniformly dispersed over the anion- and cation-deficient NaCl matrix. Our discovery might have promising implications for synthetic chemistry, indicating the possibility of preparation of complex polyoxocuprates by chemical vapor transport (CVT) techniques that emulate formation of minerals in high-temperature volcanic fumaroles.
Spatial characteristics and economic value of threatened species (Khaya ivorensis)
Authors: Chaikaew Pasicha , Adeyemi Opeyemi , Hamilton Adenule O. , Clifford Omonu
Published: April 2020

Khaya ivorensis (K. ivorensis), one of the most valuable tropical hardwood species indigenous to West and Central Africa, has been classified as a threatened tree species. However, information on its remaining population and distribution are limited. We mapped the current K. ivorensis spatial distribution, modelled the spatial autocorrelation and estimated its economic value using volume estimation and market pricing. The study was conducted in Odigbo and Irele local government areas (LGA), Ondo State, Nigeria. Spatially, localities of 97 K. ivorensis were identified across the study area and can be added into a wide range of datasets from local to global inventories. Large trees in diameter and height were statistically clustered in the north of Odigbo and assumed to relate with forest reserve management. Estimated median tree volumes were 0.39 m3 and 0.31 m3 in accordance with the allometric volume function and specific volume function, respectively. The economic values of wood varied approximately from US$111,208 to US$72,081. Findings from this study are a valuable resource for conserving this species and other threatened tree species.
Comprehensive immunogenomic landscape analysis of prognosis-related genes in head and neck cancer
Authors: Li Lei , Wang Xiao-Li , Lei Qian , Sun Chuan-Zheng , Xi Yan , Chen Ran , He Yong-Wen
Published: April 2020

Head and neck cancer is the sixth most common malignancy around the world, and 90% of cases are squamous cell carcinomas. In this study, we performed a systematic investigation of the immunogenomic landscape to identify prognostic biomarkers for head and neck squamous cell carcinoma (HNSCC). We analyzed the expression profiles of immune‐related genes (IRGs) and clinical characteristics by interrogating RNA-seq data from 527 HNSCC patients in the cancer genome atlas (TCGA) dataset, including 41 HPV+ and 486 HPV− samples. We found that differentially expressed immune genes were closely associated with patient prognosis in HNSCC by comparing the differences in gene expression between cancer and normal samples and performing survival analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to annotate the biological functions of the differentially expressed immunogenomic prognosis-related genes. Two additional cohorts from the Oncomine database were used for validation. 65, 56 differentially expressed IRGs was associated with clinical prognosis in total and HPV- samples, respectively. Furthermore, we extracted 10, 11 prognosis-related IRGs from 65, 56 differentially expressed IRGs, respectively. They were significantly correlated with clinical prognosis and used to construct the prognosis prediction models. The multivariable ROC curves (specifically, the AUC) were used to measure the accuracy of the prognostic models. These genes were mainly enriched in several gene ontology (GO) terms related to immunocyte migration and receptor and ligand activity. KEGG pathway analysis revealed enrichment of pathways related to cytokine−cytokine receptor interactions, which are primarily involved in biological processes. In addition, we identified 63 differentially expressed transcription factors (TFs) from 4784 differentially expressed genes, and 16 edges involving 18 nodes were formed in the regulatory network between differentially expressed TFs and the high-risk survival-associated IRGs. B cell and CD4 T cell infiltration levels were significantly negatively correlated with the expression of prognosis-related immune genes regardless of HPV status. In conclusion, this comprehensive analysis identified the prognostic IRGs as potential biomarkers, and the model generated in this study may enable an accurate prediction of survival.
A Quantitative Comparison of the Counting Significance of van Hove Integral Spectroscopy and Quasielastic Neutron Scattering
Authors: Benedetto Antonio , Kearley Gordon J.
Published: April 2020

We have recently proposed a new method to access system dynamics via neutron scattering based on measuring the elastic scattered intensity: By varying the energy band-width that impinges on the sample (also known as instrumental energy resolution), the purely elastic-scattering from this variation is the running time-integral of the intermediate scattering function (I(t)) [Benedetto and Kearley, Sci. Rep. 9, 11284, 2019]. In this correspondence we denote our method “vHI”, which stands for “van Hove Integral”. The method is now widely accepted as “valid” and here we focus on the efficiency of the vHI method compared with the standard quasi-elastic neutron scattering (QENS) method. We use a numerical Monte-Carlo simulation of an instrument that is equally capable of measuring QENS and vHI under identical conditions. For an “experiment” in which the same number of neutrons enter the instrument, we present comparisons between QENS and vHI at three levels of data-reduction. Firstly, at the raw-data level vHI achieves 100 times more neutrons at the detector than QENS. Secondly, vHI has a factor of 2 less statistical error, which would translate to an overall gain of 4 for vHI in counting-time. Lastly, we compare the distortions caused in obtaining the final I(t) via time-Fourier transform (QENS) and polynomial time-derivative (vHI). Here, the statistical error is 10 times smaller for vHI. This last comparison is the most important result where the 10 times smaller residual for vHI gives a net gain in counting time of 100 better than QENS to obtain the same underlying dynamics of the system under study.
Microbial Dysbiosis During Simian Immunodeficiency Virus Infection is Partially Reverted with Combination Anti-retroviral Therapy
Authors: Blum Faith C. , Hardy Britney L. , Bishop-Lilly Kimberly A. , Frey Kenneth G. , Hamilton Theron , Whitney James B. , Lewis Mark G. , Merrell D. Scott , Mattapallil Joseph J.
Published: April 2020

Human immunodeficiency virus (HIV) infection is characterized by a massive loss of CD4 T cells in the gastrointestinal tract (GIT) that is accompanied by changes in the gut microbiome and microbial translocation that contribute to inflammation and chronic immune activation. Though highly active antiretroviral therapy (HAART) has led to better long-term outcomes in HIV infected patients, it has not been as effective at reverting pathogenesis in the GIT. Using the simian immunodeficiency virus (SIV) infection model, we show that combination antiretroviral therapy (c-ART) partially reverted microbial dysbiosis observed during SIV infection. Though the relative abundance of bacteria, their richness or diversity did not significantly differ between infected and treated animals, microbial dysbiosis was evident via multiple beta diversity metrics: Jaccard similarity coefficient, Bray-Curtis similarity coefficient, and Yue & Clayton theta similarity coefficient. Principal coordinates analysis (PCoA) clustered SIV-infected untreated animals away from healthy and treated animals that were clustered closely, indicating that c-ART partially reversed the gut dysbiosis associated with SIV infection. Metastats analysis identified specific operational taxonomic units (OTUs) falling within the Streptococcus, Prevotella, Acinetobacter, Treponema, and Lactobacillus genera that were differentially represented across the three groups. Our results suggest that complete viral suppression with c-ART could potentially revert microbial dysbiosis observed during SIV and HIV infections.
Diagnostic challenges of posterior fossa hemangioblastomas: Refining current radiological classification scheme
Authors: Kim Eui Hyun , Moon Ju Hyung , Kang Seok-Gu , Lee Kyu Sung , Chang Jong Hee
Published: April 2020

Hemangioblastomas (HBMs) are known to exhibit very typical radiological features and thus classified by well-established radiological classification scheme. We reviewed our series of posterior fossa HBMs in order not only to evaluate the relevance of current classification scheme, but also to possibly refine it. Also, we added descriptions on several cases with unusual radiological magnetic resonance imaging (MRI) findings in which differential diagnosis was challenging. We retrospectively reviewed preoperative MRI of 118 patients with pathologically diagnosed posterior fossa HBMs at our institution between 2002 and 2015. Total 128 tumors were included to this study and classified into four categories based on the presence and nature of cystic components: extratumoral cystic (Type Ce, classical cystic with a mural nodule), intratumoral cystic (Type Ci), mixed cystic (Type Cm), and solid (Type S). The association with von Hippel-Lindau (VHL) disease was also investigated. In 118 patients (65 male and 53 female), 79 (66.9%) had solitary HBMs and 39 (33.1%) were diagnosed with VHL disease. Type Ce with typical radiological findings was the most prevalent type of HBM (63.3%), followed by Type S (21.1%). HBMs with intratumoral cysts were uncommon (Type Ci, 11.7%) and mixed extratumoral and intratumoral cysts (Type Cm) accounted for only 3.9%. No intergroup differences were observed in the proportions of each subtype between the solitary and VHL disease-associated HBMs. The blood loss was much lower in Type Ce than in other subtypes. In Type Cm, radical resection was often challenging as the differentiation between intratumoral and extratumoral cysts was difficult resulting in incomplete resection. Refined radiological classification scheme is more practical because it does not only help surgeons determine whether the cystic wall should be removed or not, but also covers cases with atypical radiological presentations. For solid and extraparenchymal HBMs, differential diagnosis is more difficult as well as very critical as surgical removal is often very challenging.