bluuebunny/crossref_metadata_2025 huggingface dataset:
A sequential niche multimodal conformational sampling algorithm for protein structure prediction
Authors: Xia Yu-Hao , Peng Chun-Xiang , Zhou Xiao-Gen , Zhang Gui-Jun
Published: July 2021

Motivation

Massive local minima on the protein energy landscape often cause traditional conformational sampling algorithms to be easily trapped in local basin regions, because they find it difficult to overcome high-energy barriers. Also, the lowest energy conformation may not correspond to the native structure due to the inaccuracy of energy models. This study investigates whether these two problems can be alleviated by a sequential niche technique without loss of accuracy.

Results

A sequential niche multimodal conformational sampling algorithm for protein structure prediction (SNfold) is proposed in this study. In SNfold, a derating function is designed based on the knowledge learned from the previous sampling and used to construct a series of sampling-guided energy functions. These functions then help the sampling algorithm overcome high-energy barriers and avoid the re-sampling of the explored regions. In inaccurate protein energy models, the high-energy conformation that may correspond to the native structure can be sampled with successively updated sampling-guided energy functions. The proposed SNfold is tested on 300 benchmark proteins, 24 CASP13 and 19 CASP14 FM targets. Results show that SNfold correctly folds (TM-score ≥ 0.5) 231 out of 300 proteins. In particular, compared with Rosetta restrained by distance (Rosetta-dist), SNfold achieves higher average TM-score and improves the sampling efficiency by more than 100 times. On several CASP FM targets, SNfold also shows good performance compared with four state-of-the-art servers in CASP. As a plug-in conformational sampling algorithm, SNfold can be extended to other protein structure prediction methods.

Availability and implementation

The source code and executable versions are freely available at https://github.com/iobio-zjut/SNfold.

Supplementary information

Supplementary data are available at Bioinformatics online.
UCSC Cell Browser: visualize your single-cell data
Authors: Speir Matthew L , Bhaduri Aparna , Markov Nikolay S , Moreno Pablo , Nowakowski Tomasz J , Papatheodorou Irene , Pollen Alex A , Raney Brian J , Seninge Lucas , Kent W James , Haeussler Maximilian
Published: July 2021

As the use of single-cell technologies has grown, so has the need for tools to explore these large, complicated datasets. The UCSC Cell Browser is a tool that allows scientists to visualize gene expression and metadata annotation distribution throughout a single-cell dataset or multiple datasets.

Availability and implementation

We provide the UCSC Cell Browser as a free website where scientists can explore a growing collection of single-cell datasets and a freely available python package for scientists to create stable, self-contained visualizations for their own single-cell datasets. Learn more at https://cells.ucsc.edu.

Supplementary information

Supplementary data are available at Bioinformatics online.
Frailty among chronic kidney disease patients on the kidney transplant waiting list: the sex–frailty paradox
Authors: Pérez-Sáez María José , Arias-Cabrales Carlos E , Dávalos-Yerovi Vanesa , Redondo Dolores , Faura Anna , Vera María , Bach Anna , Pedreira Guillermo , Junyent Ernestina , Crespo Marta , Marco Ester , Rodríguez-Mañas Leocadio , Pascual Julio ,   , for the FRAIL-MAR Study Group
Published: July 2021

Background

Frailty is defined as decreased physiologic reserve and resistance to stressors that predisposes patients towards poor health results. Its prevalence in chronic kidney disease (CKD) patients who are kidney transplant (KT) candidates is high. Frailty is associated with a higher rate of complications and mortality after transplant. It is unknown whether frailty phenotype differs depending on sex in this population.

Methods

This was a prospective longitudinal study of 455 KT candidates evaluated for frailty by physical frailty phenotype at the time of inclusion on the KT waiting list. Pre-frailty was defined as the presence of two criteria and frailty as three or more criteria. Univariate and multivariate analyses searched for associations of frailty status, frailty components and gender differences.

Results

Thirty percent of the total cohort resulted to be pre-frail (20%) or frail (10.3%), but disparities were observed between sexes, with 22.5% of men and 47.2% of women falling into one of these categories. Among frailty criteria, women presented with a higher percentage of exhaustion (39.6% versus 17%) and slowness (22.2% versus 9.6%) compared with men. Comorbidity burden was higher among frail men, whereas social factors were poorer between frail women. Disability was common among those patients who were frail, both men and women.

Conclusions

Frailty is twice as frequent in advanced CKD women as men. Frailty criteria distribution and phenotype seem to differ among sexes, which might have implications in terms of specific and individualized interventions to improve their status before transplantation.
Identification of Ulcers and Erosions by the Novel Pillcam™ Crohn’s Capsule Using a Convolutional Neural Network: A Multicentre Pilot Study
Authors: Ferreira João Pedro Sousa , de Mascarenhas Saraiva Miguel José da Quinta e Costa , Afonso João Pedro Lima , Ribeiro Tiago Filipe Carneiro , Cardoso Hélder Manuel Casal , Ribeiro Andrade Ana Patrícia , de Mascarenhas Saraiva Miguel Nuno Gameiro , Parente Marco Paulo Lages , Natal Jorge Renato , Lopes Susana Isabel Oliveira , de Macedo Guilherme Manuel Gonçalves
Published: July 2021

Background and Aims

Capsule endoscopy is a central element in the management of patients with suspected or known Crohn’s disease. In 2017, PillCam™ Crohn’s Capsule was introduced and demonstrated to have greater accuracy in the evaluation of extension of disease in these patients. Artificial intelligence [AI] is expected to enhance the diagnostic accuracy of capsule endoscopy. This study aimed to develop an AI algorithm for the automatic detection of ulcers and erosions of the small intestine and colon in PillCam™ Crohn’s Capsule images.

Methods

A total of 8085 PillCam™ Crohn’s Capsule images were extracted between 2017 and 2020, comprising 2855 images of ulcers and 1975 erosions; the remaining images showed normal enteric and colonic mucosa. This pool of images was subsequently split into training and validation datasets. The performance of the network was subsequently assessed in an independent test set.

Results

The model had an overall sensitivity and specificity of 90.0% and 96.0%, respectively. The precision and accuracy of this model were 97.1% and 92.4%, respectively. In particular, the algorithm detected ulcers with a sensitivity of 83% and specificity of 98%, and erosions with sensitivity and specificity of 91% and 93%, respectively.

Conclusion

A deep learning model capable of automatically detecting ulcers and erosions in PillCam™ Crohn’s Capsule images was developed for the first time. These findings pave the way for the development of automatic systems for detection of clinically significant lesions, optimizing the diagnostic performance and efficiency of monitoring Crohn’s disease activity.
Safety and efficacy of flecainide associated with beta-blockers in arrhythmogenic right ventricular cardiomyopathy
Authors: Rolland Thomas , Badenco Nicolas , Maupain Carole , Duthoit Guillaume , Waintraub Xavier , Laredo Mikael , Himbert Caroline , Frank Robert , Hidden-Lucet Francoise , Gandjbakhch Estelle
Published: July 2021

Aims

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy associated with a high risk of ventricular arrhythmia (VA). Current guidelines recommend beta-blockers as first-line medical therapy and if ineffective, sotalol or amiodarone. We describe our experience, as a tertiary centre for ARVC, with the effectiveness and tolerance of flecainide in addition to beta-blockers to prevent VA in ARVC.

Methods and results

We retrospectively included 100 consecutive ARVC patients who received flecainide with beta-blockers between May 1999 and November 2017. Treatment persistence and related side effects were assessed, as was VA-free survival on treatment, 24-h Holter monitoring and programmed ventricular stimulation (PVS) off- and on-treatment. Tolerance was good, with 10% flecainide discontinuations (lack of efficacy in six, atrial fibrillation in one, and side effects in three). No Brugada-induced electrocardiography pattern on flecainide or haemodynamic impairment was reported. Premature ventricular contraction burden at 24-h Holter monitoring was significantly decreased under treatment [median 415 (interquartile range, IQR 97–730) vs. 2370 (1572–3400) at baseline, P < 0.0001, n = 46]. Among the 33 patients with PVS under treatment, PVS was positive in 40% on-treatment vs. 94% off-treatment (P < 0.001). During a median follow-up of 47 months (IQR 23–73), 22 patients presented sustained VA on treatment, corresponding to an event rate of 5% [95% confidence interval (CI) (0.6–9)] at 1 year and 25% [95% CI (14–35)] at 5 years under treatment. No patient died.

Conclusion

This study suggests that flecainide and beta-blockers association is complementary to implantable cardioverter-defibrillator and catheter ablation and is safe for treating persistent symptomatic VA in patients with ARVC.
Stronger alcohol-violence association when adolescents drink less? Evidence from three Nordic countries
Authors: Moan Inger Synnøve , Bye Elin K , Rossow Ingeborg
Published: July 2021

Background

Since 2000, adolescents’ alcohol use and heavy episodic drinking (HED) have declined in the Nordic countries. However, little is known about corresponding trends in alcohol-related harm and possible changes in the alcohol-harm association. The aims are to examine (i) whether the decline in HED was accompanied by a decline in alcohol-related violence (AV) and (ii) whether the strength of the HED-AV association changed concomitant with the decline.

Methods

Analysis of data from the European School Survey Project on Alcohol and Other Drugs (ESPAD), conducted among 15–16-year-olds in Iceland, Norway and Sweden in 2007 and 2015 (n = 17 027). Changes in proportions of AV and alcohol use past 12 months, and mean frequency of HED past 30 days were examined using Pearsons χ2-test and F-test, respectively. The HED-AV associations were estimated using logistic regression analysis.

Results

HED and AV proportions decreased from 2007 to 2015 in all countries. Among current drinkers (n = 8927), both HED frequency and AV proportion decreased in Norway (P < 0.001) and remained stable in Iceland. In Sweden, AV decreased (P < 0.001) whereas HED remained stable. The magnitude of the HED-AV association increased in Norway (Beta2015–2007 = 0.145, 95% CI 0.054–0.236), remained the same in Iceland and decreased in Sweden (Beta2015–2007 = −0.082, 95% CI −0.158 to −0.005).

Conclusions

Among youth in Iceland, Norway and Sweden, heavy episodic drinking and alcohol-related violence declined from 2007 to 2015. Among drinkers, the strength of the alcohol-violence association was moderated by the extent of heavy episodic drinking.
Long-term Trajectories of C-Reactive Protein Among Men Living With and Without HIV Infection in the Multicenter AIDS Cohort Study
Authors: Wada Nikolas I , Breen Elizabeth C , Post Wendy S , Stosor Valentina , Macatangay Bernard J , Margolick Joseph B
Published: July 2021

Background

C-reactive protein (CRP) is an inflammatory biomarker associated with all-cause mortality and morbidities such as cardiovascular disease. CRP is increased with HIV infection and thought to increase with age, though trajectories of CRP with aging have not been well characterized. We investigated trajectories of CRP in men from the Multicenter AIDS Cohort Study, according to HIV infection and HIV viral load status.

Methods

CRP measurements from 12 250 serum samples, provided by 2132 men over a span of 30 years, were categorized by HIV status at sample collection: HIV uninfected (HIV−, n = 1717), HIV infected with undetectable RNA (HIV+ suppressed, n = 4075), and detectable HIV RNA (HIV+ detectable, n = 6458). Age-related trajectories of CRP were fit to multivariable linear mixed models; we tested for differences in trajectories by HIV status.

Results

CRP increased with age in all sample groups. HIV+ detectable and HIV+ suppressed samples had higher CRP than HIV− samples throughout the observed age range of 20–70 years (p < .05). CRP concentrations at age 45 years were 38% (95% CI: 26%–50%) and 26% (15%–38%) higher in HIV+ detectable and HIV+ suppressed samples, respectively, relative to HIV− samples. HIV+ detectable samples showed more rapid linear increases with age (8% higher/decade, 0.3%–16%) than HIV− samples.

Conclusions

We observed higher concentrations of CRP across 5 decades of age in men living with HIV, and steeper increases with age in men with detectable HIV RNA, relative to HIV− men. These results are consistent with a contribution of inflammation to the higher risk of age-related comorbidities with HIV infection.
Risks and rewards of the surgical treatment of lung cancer in octogenarians
Authors: Saftic Igor , Bille Andrea , Asemota Nicole , Berjon de la Vega Loreto , Routledge Tom , King Juliet , Phipps Karen Harrison , Pilling John
Published: July 2021

OBJECTIVES

Surgeons will face an increasing number of octogenarians with lung cancer potentially curable by surgery. The goal of this study was to evaluate short- and long-term outcomes after lung resection.

METHODS

We performed a single-centre study of consecutive patients ≥80 years old, surgically treated for suspected lung cancer between 2009 and 2016. Age, sex, performance status, lung function, surgical approach, type of lung resection, complications, in-hospital and 30- and 90-day deaths and long-term survival were analysed.

RESULTS

Two hundred and fifty-seven patients were enrolled. The median age was 82 years (range 80–97). One hundred and thirty-four patients were treated by thoracotomy and 123 by video-assisted thoracic surgery [10 (8.1%) converted]. Two hundred and thirty-two underwent lobar resection and 25 underwent sublobar resection. There were no intraoperative deaths and 9 admissions to the intensive therapy unit; 112 (43.6%) patients suffered complications: More complications occurred after lobar versus after sublobar resections [45.7% vs 24% (P = 0.037)] and in those with chronic obstructive pulmonary disease (COPD) [57.4% vs 40% (P = 0.02)]. The 30-day mortality was 3.9% (n = 10) and the 90-day mortality was 6.22% (n = 16). One hundred and sixty-seven patients died during the study period; patients with non-small-cell lung cancer (n = 233) had a median survival of 46.5 months with 67.2% alive at 2 years and 40.8% at 5 years. Pathological stage and R status were independent prognostic factors for survival.

CONCLUSIONS

Surgery for malignancies in octogenarians is feasible and safe with good long-term outcomes. The risk of postoperative complications, especially in those with COPD, is high but can be minimized with sublobar resection. Postoperative mortality is acceptable, and long-term survival is primarily governed by lung cancer stage. Age is no reason to deny patients surgery for early-stage disease.
Antimicrobial use in hospitalized patients: a multicentre point prevalence survey across seven hospitals in Ghana
Authors: Labi Appiah-Korang , Obeng-Nkrumah Noah , Dayie Nicholas T K D , Egyir Beverly , Sampane-Donkor Eric , Newman Mercy Jemima , Opintan Japheth Awuletey
Published: July 2021

Background

Antimicrobial resistance (AMR) is a public health crisis of global proportions. Data is required to understand the local drivers of antimicrobial resistance and support decision-making processes including implementation of appropriate antimicrobial stewardship strategies.

Objectives

To measure antimicrobial usage in hospitals in Ghana.

Methods

Using the Global Point Prevalence instruments and processes, we conducted point prevalence surveys across AMR surveillance sentinel hospitals in Ghana, between September and December 2019. Hospital records of all inpatients on admission at 0800 hours on a specific day were reviewed for antimicrobial use at the time of the survey. Data on antibiotic use, including indication for use and quality of prescribing were recorded.

Results

Overall prevalence of antibiotic use across the sentinel sites was 54.9% (n = 1591/2897), ranging between 48.4% (n = 266/550) and 67.2% (n = 82/122). The highest prevalence of antibiotic use 89.3% (n = 25/28) was observed in adult ICUs. The average number of antibiotics prescribed per patient was 1.7 (n = 1562/2620), with the majority (66%, n = 728/2620) administered via the parenteral route. The five most-commonly used antibiotics were metronidazole (20.6%, n = 541/2620), cefuroxime (12.9%, n = 338/2620), ceftriaxone (11.8%, n = 310/2620), amoxicillin/clavulanic acid (8.8%, n = 231/2620) and ciprofloxacin (7.8%, n = 204/2620). The majority (52.2%; n = 1367/2620) of antibiotics were prescribed to treat an infection, whilst surgical prophylaxis accounted for 26.1% (n = 684/2620).

Conclusions

We observed a high use of antibiotics including metronidazole and cephalosporins at the participating hospitals. Most antibiotics were empirically prescribed, with low use of microbiological cultures. High usage of third-generation cephalosporins especially for community-acquired infections offers an opportunity for antibiotic stewardship interventions.
The First Climate Judgment before the Norwegian Supreme Court: Aligning Law with Politics
Authors: Voigt Christina
Published: July 2021

On 22 December 2020, the Norwegian Supreme Court ruled on its first climate case. It dealt with the claim that petroleum licences, issued by the Norwegian government, violate the ‘right to a healthy environment’ as contained in the Norwegian Constitution. The Court rejected the claim and found that the constitutional protection of the environment applies not as a right but as a substantive limit to governmental action, and only in very limited circumstances. Rather than taking the opportunity to give guidance on this constitutional provision, the Court provided a judgment that aligned law with the current politics in favour of continuous petroleum extraction on Norwegian territory.
Role ofSalix reiniipatches in spatio-temporal patterns of cohabitants on a Japanese volcano
Authors: Matsuda Miyuki , Tsuyuzaki Shiro
Published: July 2021

Shrub patches often support the colonizers particularly under stressful and/or disturbed environments. The intensities of stresses and disturbances on mountains are often related to an elevation gradient and are decreased by shrub patches (canopy and litter). We aim to clarify these relationships by using shrub patches at different elevations on a volcano. We monitored all shoots in plots established inside and outside of patches of Salix reinii (Salicaceae) and their related environments, such as temperature, light, moisture and chemistry, at three elevations on Mount Koma (1131 m a.s.l.), northern Japan, from early spring in 2005 to summer in 2006. The patch structures were evaluated by area, branch density and litter thickness. The structures of shrub patches did not differ among the elevations. The patches increased the diversity of rare species, by an overall increase in plant species richness. The moisture, nitrogen and phosphate contents in the patches were higher than outside of patches. The effects of shrub patches on the cohabitants were overall positive, although the effects were negative on seedling abundance, shoot survival and flowering. These results suggest that the growth patterns of shrub patches determine the plant community structures and facilitate plant diversity.
Large-scale clustering amongst Fermi blazars; evidence for axis alignments?
Authors: Marchã M J M , Browne I W A
Published: July 2021

We find evidence for large-scale clustering amongst Fermi-selected BL Lac objects but not amongst Fermi-selected flat spectrum radio quasars (FSRQs). Using two-point correlation functions, we have investigated the clustering properties of different classes of objects from the Fermi–LAT(Large Area Telescope) 4FGL catalogue. We wanted to test the idea based on optical polarization observations that there might be large volumes of space in which AGN axes are aligned. To do this, we needed a clean sample of blazars as these are objects with their jet axes pointing towards the observer and Fermi sources provide such a sample. We find that high latitude Fermi sources taken as a whole show a significant clustering signal on scales up to 30°. To investigate if all blazars behave in the same way we used he machine learning classifications from the literature, which are based only on gamma-ray information, to separate BL Lac-like objects from FSRQ-like objects. A possible explanation for the clustering signal we find amongst the BL Lac-like objects is that there are indeed large volumes of space in which AGN axes are aligned. This signal might be washed out in FSRQs since they occupy a much larger volume of space. Thus, our results support the idea that large scale polarization alignments could originate from coherent alignments of AGN axes. We speculate that these axis alignments may be related to the well-known intrinsic alignments of galaxy optical position angles.
The BACCO simulation project: a baryonification emulator with neural networks
Authors: Aricò Giovanni , Angulo Raul E , Contreras Sergio , Ondaro-Mallea Lurdes , Pellejero-Ibañez Marcos , Zennaro Matteo
Published: July 2021

We present a neural network emulator for baryonic effects in the non-linear matter power spectrum. We calibrate this emulator using more than 50 000 measurements in a 15D parameter space, varying cosmology and baryonic physics. Baryonic physics is described through a baryonification algorithm, which has been shown to accurately capture the relevant effects on the power spectrum and bispectrum in state-of-the-art hydrodynamical simulations. Cosmological parameters are sampled using a cosmology-rescaling approach including massive neutrinos and dynamical dark energy. The specific quantity we emulate is the ratio between matter power spectrum with baryons and gravity only, and we estimate the overall precision of the emulator to be $2\!-\!3{{\ \rm per\ cent}}$, at scales $k \lt 5 \, h\, {\rm Mpc}^{-1}$ and redshifts 0 < z < 1.5. We obtain an accuracy of $1\!-\!2{{\ \rm per\ cent}}$, when testing the emulator against a collection of 74 different cosmological hydrodynamical simulations and their respective gravity-only counterparts. We also show that only one baryonic parameter, namely Mc, which sets the gas fraction retained per halo mass, is enough to have accurate predictions of most of the baryonic feedbacks at a given epoch. Our emulator is publicly available at http://www.dipc.org/bacco.
Compensation of differential dispersion: application to multiband stellar interferometry
Authors: Pannetier Cyril , Mourard Denis , Cassaing Frédéric , Lagarde Stéphane , Le Bouquin Jean-Baptiste , Monnier John , Sturmann Judit , Ten Brummelaar Theo
Published: July 2021

With the aim of pushing the limiting magnitude of interferometric instruments, the need for wide-band detection channels and for a coordinated operation of different instruments has considerably grown in the field of long-baseline interferometry. For this reason, the Center for High Angular Resolution Astronomy (CHARA), an array of six telescopes, requires a new configuration of longitudinal dispersion compensators to keep the fringe contrast above 95 per cent simultaneously in all spectral bands, while preserving the transmission above 85 per cent. In this paper, we propose a new method for defining the longitudinal dispersion compensators (LDC) suited for multiband observations. A literal approximation of the contrast loss resulting from the dispersion residues enables us to define a general criterion for fringe contrast maximization on several bands simultaneously. The optimization of this criterion leads to a simple solution with only two LDC stages per arm and existing differential delay lines, to the glass choice and a simple linear formula for thickness control of all these media. A refined criterion can also take into account glass transmission. After presenting this criterion, we give the optimal solution (medium, configuration) and its expected performance for the planned observing modes on CHARA.
PIP-SNP: a pipeline for processing SNP data featured as linkage disequilibrium bin mapping, genotype imputing and marker synthesizing
Authors: Zhang Wenchao , Kang Yun , Dai Xinbin , Xu Shizhong , Zhao Patrick X
Published: July 2021

Genome-wide association study data analyses often face two significant challenges: (i) high dimensionality of single-nucleotide polymorphism (SNP) genotypes and (ii) imputation of missing values. SNPs are not independent due to physical linkage and natural selection. The correlation of nearby SNPs is known as linkage disequilibrium (LD), which can be used for LD conceptual SNP bin mapping, missing genotype inferencing and SNP dimension reduction. We used a stochastic process to describe the SNP signals and proposed two types of autocorrelations to measure nearby SNPs’ information redundancy. Based on the calculated autocorrelation coefficients, we constructed LD bins. We adopted a k-nearest neighbors algorithm (kNN) to impute the missing genotypes. We proposed several novel methods to find the optimal synthetic marker to represent the SNP bin. We also proposed methods to evaluate the information loss or information conservation between using the original genome-wide markers and using dimension-reduced synthetic markers. Our performance assessments on the real-life SNP data from a rice recombinant inbred line (RIL) population and a rice HapMap project show that the new methods produce satisfactory results. We implemented these functional modules in C/C++ and streamlined them into a web-based pipeline named PIP-SNP (https://bioinfo.noble.org/PIP_SNP/) for processing SNP data.
ECOA-7. Conserved cell-lineage controlled chromatin accessibility in human and mouse glioblastoma stem cells predicts functionally distinct subgroups
Authors: Lu Xi , Maturi Naga Prathyusha , Jarvius Malin , Zhao Linxuan , Xie Yuan , Tan E-Jean , Xing Pengwei , Fryknäs Mårten , Uhrbom Lene , Chen Xingqi
Published: July 2021

There is ample support for developmental control of glioblastoma stem cells (GSCs), and a deeper knowledge of their epigenetic regulation could be central to more efficient glioblastoma (GBM) therapies. For this purpose, we analyzed the chromatin-accessibility landscape of nine mouse GSC cultures of defined cell of origin and 60 patient-derived GSC cultures by assay for transposase-accessible chromatin using sequencing (ATAC-seq). This uncovered an epigenetic variability of both mouse and human GSC cultures that differed from transcriptome clusters. Both mouse and human chromatin accessibility-guided clusters were predominantly determined by distal regulatory elements, displayed unique sets of transcription factor motif enrichment, and exhibited different functional and drug-response properties. Cross-species analysis of distal regulatory element regions in accessible chromatin of mouse and human cultures revealed conserved epigenetic regulation of GSCs.
ECOA-9. Integration of molecular and methylation classifications yields three meningioma groups and suggests chromosome 1p loss may be critical to the aggressive group
Authors: Bayley James , Hadley Caroline , Harmanci Arif , Harmanci Akdes , Klisch Tiemo , Patel Akash
Published: July 2021

Next-generation sequencing has deepened our understanding of meningiomas, particularly those that behave aggressively. Classifications using either DNA methylation profiling or RNA-sequencing predict tumor behavior more reliably than WHO grade, and segregate common meningioma features similarly, implying possible overlap between classifications. In this study, we performed DNA methylation profiling, RNA-sequencing, and whole-exome sequencing on 110 primary meningiomas (90 WHO I, 20 WHO II). Unsupervised non-negative matrix factorization demonstrated three epigenetic types which were highly concordant with our published transcriptional types (87.3% concordance). Two additional classifications (one using 1p/22 loss, the other merlin expression/chromosomal instability) were also highly concordant and an overall meningioma group (MenG) classification was assigned integrating all four together. MenG A and B rarely recur, while MenG C behave aggressively (median recurrence free survival (RFS) of 3.1 years), even after gross total resection (median RFS 4.2 years). MenG A tumors retain Merlin expression (no chromosome loss or NF2 mutation) and harbor mutations in TRAF7, AKT1, or KLF4. Both MenG B and C are merlin-deficient, but MenG B demonstrate low rates of CNV and MenG C high rates of CNV, particularly loss of chromosome 1p. Using partial least squares regression (PLS), we explored how gene expression correlated with promoter methylation and CNV, thereby classifying genes which correlated closely as ‘methylation-driven’ or ‘CNV-driven’. Overall, there were more methylation-driven (5.7%) than CNV-driven (2.9%) genes. Differentially expressed genes (DEGs) were enriched for both methylation- and CNV-driven genes at similar proportions (10.6% and 5.8%), but DEGs unique to MenG C were significantly enriched for CNV-driven (23.7%), but not methylation-driven (4.7%) genes, primarily due many MenG C DEGs on chromosome 1p. Overall, this work suggests three underlying meningioma groups which are identifiable through methylation, transcriptional, or genetic/cytogenetic profiling and warrants exploration of the role of chromosome 1p in group that behaves aggressively.
MOMC-3. Hypermethylation and overexpression of HOX genes are poor prognosticators in Lower-Grade Glioma
Authors: Mamatjan Yasin , Voisin Mathew , Nassiri Farshad , Moraes Fabio , Bunda Severa , Salih Mira , Aldape Kenneth , Zadeh Gelareh
Published: July 2021

Diffuse gliomas represent over 80% of malignant brain tumors ranging from low-grade to aggressive high-grade lesions. Molecular characterization of these tumors led to the development of new classification system comprising specific glioma subtypes. While this provides novel molecular insight into gliomas it does not fully explain the variability in patient outcome. To identify and characterize a predictive signature of outcome in diffuse gliomas, we utilized an integrative molecular analysis (methylation, mRNA, copy number variation (CNV) and mutation data) using multiple molecular platforms, including a total of 310 IDH mutant glioma samples from University Health Network (UHN) and German Cancer Research Center (DKFZ) together with 419 samples from The Cancer Genome Atlas (TCGA). Cox regression analysis of methylation data from the UHN cohort identified CpG-based signatures that split the glioma cohort into two prognostic groups strongly predicting survival (p-value < 0.0001). The CpG-based signatures were reliably validated using two independent datasets from TCGA and DKFZ cohorts (both p-values < 0.0001). The results show that the methylation signatures that predict poor outcome also correlated with G-CIMP low status, elevated CNV instability and hypermethylation of a set of HOX gene probes. Further study in diffuse lower-grade glioma (LGG) using integrated mRNA and methylation (iRM) analyses showed that parallel HOX gene overexpression and hypermethylation in the same direction were significantly associated with increased mutational load, high aneuploidy and worse survival (p-value < 0.0001). Furthermore, this iRM high group was characterized by a 7-HOX gene signature showed significant survival differences not only in IDH mutant LGG but also in IDH wildtype LGG. These results demonstrate the importance of HOX genes in predicting the outcome of diffuse gliomas to identify relevant molecular subtyping independent of histology.
OTEH-1. Alternative RNA splicing modulates composition of ribosomes and determines spatial phenotype of glioblastoma cells
Authors: Pavlyukov Marat , Larionova Tatyana , Bastola Soniya , Shender Victoria , Nakano Ichiro , Shakhparonov Michail
Published: July 2021

Glioblastoma (GBM) is an extremely heterogeneous tumor and its different regions are populated with phenotypically distinct types of cancer cells. However, it is still unclear how multiple GBM populations arise from the originally homogenous group of tumor precursor cells. Here we showed that GBM cells from the core and edge of the tumor have different composition of ribosomes due to the alternative RNA splicing of multiple ribosomal genes with highest differences observed for RPL22L1. We found that cells at the edge of the tumor express classical isoform of RPL22L1 (RPL22L1a) while core cells have a novel RPL22L1b isoform. RPL22L1b appears due to low pH condition at the core of the tumor. It allows cells to survive during acidosis, promotes more aggressive phenotype in vivo and correlate with worse patient outcome. Mechanistically, RPL22L1b binds to lncRNA MALAT1 in the nucleus and induces its degradation enhancing stemness of GBM cells. On the other hand, RPL22L1a interacts with ribosomes in cytoplasm and upregulates p53 translation favoring less aggressive edge phenotype of GBM. The splicing switch between RPL22L1 isoforms is regulated by SRSF4 proteins. We identified a small molecule compound that inhibits SRSF4 and impairs splicing of RPL22L1, inducing apoptosis of GBM cells and decreasing tumor growth in vivo. Altogether, our data unraveled the mechanism by which less aggressive edge-like GBM cells acquire more malignant core-like phenotype during tumor growth. It may also explain discrepancies between proteome and transcriptome of GBM cell populations. Targeting this pathway may help to decrease tumor heterogeneity and eliminate therapy resistant cells at the tumor core.

Work was supported by the Russian Science Foundation grant 19-44-02027.
OTME-16. Polio virotherapy of murine brain tumors causes microglia/macrophage proliferation and inflammation that is potentiated by immune checkpoint blockade
Authors: Yang Yuanfan , Brown Michael , Stevenson Kevin , López Giselle , Kornahrens William , Zhang Gao , Gromeier Matthias
Published: July 2021

PVSRIPO is a novel viral immunotherapy that has shown evidence of efficacy in a phase I clinical trial for recurrent GBM, resulting in 21% survival rate at 36 months following treatment. To improve clinical response rate, it is critical to resolve the mechanisms of action and therapy resistance in vivo, thereby designing effective combination therapy strategies.

We used immunocompetent mouse models of glioma (CT2A) and metastatic melanoma (B16) to dissect early and late events following virotherapy with PVSRIPO. A blinded systematic review of the pathology from 62 intracranial tumors, collected on different days following PVSRIPO (or control) treatment, was performed. An overall treatment effect, measured by tumor shrinkage, dis-cohesive growth pattern, microglia enrichment, was present in 88% of tumors on day 8, but the tissue response rate fell to 42% on days 10 & 12, and 14% on day 15. The control group showed no treatment effect throughout. RNAseq from the same set of samples showed acute induction of type-I interferon-related inflammation that faded with time in Gene Set Enrichment Analysis. This suggests that sustaining adaptive antitumor immunity elicited by immediate intratumor type-I IFN-dominant inflammation is critical to long term remission. Careful review of the post treatment pathology revealed an early enrichment of both T cells and microglia in the tumor microenvironment with a high Ki-67 proliferation index. We propose that the PVSRIPO therapy effect is dependent on macrophage/microglia mediated cellular immune response, likely in response to direct viral infection. This suggests potential therapeutic interventions, including blockade of the PD1:PD-L1 immune checkpoint, to potentiate antitumor CD8+T cells in response to PVSRIPO therapy. Indeed, combination therapy with αPD-L1 antibody in the CT2A model showed higher long term remission (37%, n=11), compared to either monotherapy; this effect is CD8+T cell- and macrophage-dependent, demonstrated by depletion studies in vivo.
Interdisciplinary approaches based on imaging radar enable cutting-edge cultural heritage applications
Authors: Chen Fulong , Guo Huadong , Tapete Deodato , Masini Nicola , Cigna Francesca , Lasaponara Rosa , Piro Salvatore , Lin Hui , Ma Peifeng
Published: July 2021

By analysing the technical advantages and characteristics of imaging radar in cultural heritage, we provide new insights for the future development of cutting-edge Digital Heritage approaches through technical integration and interdisciplinary synergy.
The Effects of Ideological and Ethnoracial Identity on Political (Mis)Information
Authors: Crowder-Meyer Melody , Ferrín Mónica
Published: July 2021

There is much concern today about the spread of fake news and the misinformation it can produce among the public. In this article, we investigate how the American public interprets accurate and inaccurate statements from the news. Moving beyond partisanship, we theorize that ideological and ethnoracial identities also shape individuals’ interpretations of the news. We argue that people have incentives to interpret information they encounter in ways that favor their ideological and ethnoracial ingroups and that these incentives are particularly strong when ideological and ethnoracial identities align. Using a survey that asks respondents to classify statements from news stories as facts or opinions, we find support for these hypotheses. Liberals and conservatives, and white, Black, and Hispanic respondents, more often classify as factual statements that favor their ingroup’s interests while classifying information opposing their ingroup’s interests as opinions. Holding cross-cutting ethnoracial and ideological identities diminishes these effects, while identities that align produce stronger ingroup biases in information processing, particularly among whites. Our study reveals that it is not only partisanship but also ideological and ethnoracial identities that shape how Americans interpret the news, and therefore how informed, or misinformed, they are.
Inpatient Treatment of People With Schizophrenia: Quantifying Clinical Change Using the Health of the Nation Outcome Scales
Authors: Lay Barbara , Roser Patrik , Kawohl Wolfram
Published: July 2021

Schizophrenia can require hospital inpatient care in crisis periods or times of severe symptoms, although the length of hospital stays has been considerably reduced in the last few decades. Evidence on individual outcomes under routine psychiatric practice conditions is sparse. This study aims to evaluate the outcomes of inpatient treatment in patients with schizophrenia using the reliable and clinically significant change approach. We used routinely collected Health of the Nation Outcome Scales (HoNOS) data to assess the extent to which and the areas where symptomatic and functional improvement was achieved. Data from 1783 schizophrenia patients admitted to a large psychiatric centre in Switzerland were examined.

Mean HoNOS total score dropped from 17.9 to 11.7 (effect size 0.8) during treatment; the greatest improvements were achieved regarding symptomatic problems and aggressive, agitated behavior. According to the reliable change index formula, 24.5% of patients were to be considered improved, 73.3% unchanged and 2.2% deteriorated. In total, 56.6% were discharged from the hospital in a subclinical or mild functional state. The degree of individual improvement and time to achieve maximum symptom reduction varied considerably, depending on the patients’ functional state at admission, as did the length of hospital stay (median 28 days). Rates of readmission within 28 days (17.8%) were significantly lower in patients with clinically significant improvement, discharged in better clinical condition. These findings support reconsidering (length of) inpatient treatment within the overall framework of meaningful clinical change and subsequent treatment needs in patients with schizophrenia.
Reduced concentrations of limestone and monocalcium phosphate in diets without or with microbial phytase did not influence gastric pH, fecal score, or growth performance, but reduced bone ash and serum albumin in weanling pigs
Authors: Lagos L Vanessa , Lee Su A , Bedford Mike R , Stein Hans H
Published: July 2021

An experiment was conducted to test the hypothesis that reducing limestone and monocalcium phosphate in diets for weanling pigs by lowering the concentration of Ca and P or by including microbial phytase in the diet will reduce stomach pH and fecal score and will improve growth performance of pigs. A total of 160 weanling pigs (5.75 ± 1.04 kg) were allotted to four corn-soybean meal-based diets in a completely randomized design with five pigs per pen. Diets for phase 1 (d 1 to 15) were formulated using a 2 × 2 factorial design with 2 concentrations of Ca and P (adequate or deficient levels of total Ca and digestible P) and 2 inclusion levels of phytase (0 or 2,000 units/kg feed). Phytase was assumed to release 0.16% total Ca and 0.11% digestible P. Common diets were fed in phases 2 (d 16 to 21) and 3 (d 22 to 35). Fecal scores were recorded in phase 1 and on d 15, gastric pH was measured and a blood sample and the right femur were collected from one pig per pen. Growth performance data were recorded within each phase. Results indicated that in phase 1, at deficient dietary Ca and P, pigs fed the diet with phytase had greater (P < 0.05) average daily gain (ADG) and gain to feed (G:F) compared with pigs fed the diet without phytase, but in diets with adequate levels of Ca and P, no effect of phytase inclusion was observed (interaction, P < 0.05). Without phytase, pigs fed the diet with deficient Ca and P had reduced (P < 0.05) G:F compared with pigs fed the diet with adequate Ca and P, but if phytase was included, there was no effect of Ca and P on G:F (interaction, P < 0.05). For phases 2 and 3, and from d 1 to 35, no differences among dietary treatments were observed for ADG or G:F. Bone ash was greater (P < 0.05) in pigs fed diets with adequate Ca and P than in pigs fed diets with deficient Ca and P, but no effect of phytase inclusion was observed on bone ash. Concentrations of Ca and P did not affect stomach pH or fecal score, but pigs fed diets with phytase tended (P < 0.10) to have reduced stomach pH and fecal score compared with pigs fed diets without phytase. Pigs fed diets with adequate Ca and P had greater (P < 0.05) albumin in serum than pigs fed the Ca- and P-deficient diets. In conclusion, phytase inclusion in phase 1 diets may reduce diarrhea, but lowering Ca and P does not reduce stomach pH or fecal score and decreases bone ash, although growth performance during the entire weanling period is not affected.
Ethnography and user-centered design to inform context-driven implementation
Authors: Haines Emily R , Kirk M Alexis , Lux Lauren , Smitherman Andrew B , Powell Byron J , Dopp Alex , Stover Angela M , Birken Sarah A
Published: July 2021

Despite pervasive findings pointing to its inextricable role in intervention implementation, context remains poorly understood in implementation science. Existing approaches for describing context (e.g., surveys, interviews) may be narrow in scope or superficial in their elicitation of contextual data. Thus, in-depth and multilevel approaches are needed to meaningfully describe the contexts into which interventions will be implemented. Moreover, many studies assess context without subsequently using contextual information to enhance implementation. To be useful for improving implementation, though, methods are needed to apply contextual information during implementation. In the case example presented in this paper, we embedded an ethnographic assessment of context within a user-centered design approach to describe implementation context and apply that information to promote implementation. We developed a patient-reported outcome measure-based clinical intervention to assess and address the pervasive unmet needs of young adults with cancer: the Needs Assessment & Service Bridge (NA-SB). In this paper, we describe the user-centered design process that we used to anticipate context modifications needed to deliver NA-SB and implementation strategies needed to facilitate its implementation. Our ethnographic contextual inquiry yielded a rich understanding of local implementation context and contextual variation across potential scale-up contexts. Other methods from user-centered design (i.e., translation tables and a design team prototyping workshop) allowed us to translate that information into specifications for NA-SB delivery and a plan for implementation. Embedding ethnographic methods within a user-centered design approach can help us to tailor interventions and implementation strategies to their contexts of use to promote implementation.
Genetic and other associations with pain: a literature review of potential identifiers for significant pain after total knee arthroplasty
Authors: Ryan Patrick M. , Mensch Kenneth , Catlett Sean J.
Published: July 2021

Osteoarthritis of the knee is one of the leading causes of disability and work limitations in the United States, resulting in significantly decreased work productivity and loss of work. The definitive treatment of choice for end-stage osteoarthritis is total knee arthroplasty. However, up to 34% of patients who undergo TKA experience chronic pain. Long-term pain continues to pose a significant burden and directly undermines the goal in treatment of patients with osteoarthritis, and persistent postoperative pain is a major concern to the orthopaedic community. Finding ways to reduce the number of patients experiencing persistent postoperative pain, as well as reducing the severity of the pain felt, is absolutely necessary. There is a growing cohort of evidence that suggests that the experience of pain is felt differently among patients, and there are many factors that may play a role in this experience. The difference in experience may have a genetic basis and, in the context of the growing opioid crisis in the United States, these genetic differences may explain variations in opioid effectiveness as well. This review examines the current literature that identifies specific factors responsible for the development of pain, including ethnicity, race, psychosocial, and, most notably, genetic factors.