bluuebunny/crossref_metadata_2025_split huggingface dataset:
An automated computational image analysis pipeline for histological grading of cardiac allograft rejection
Authors: Peyster Eliot G , Arabyarmohammadi Sara , Janowczyk Andrew , Azarianpour-Esfahani Sepideh , Sekulic Miroslav , Cassol Clarissa , Blower Luke , Parwani Anil , Lal Priti , Feldman Michael D , Margulies Kenneth B , Madabhushi Anant 
Published: April 2021

Abstract

Aim
Allograft rejection is a serious concern in heart transplant medicine. Though endomyocardial biopsy with histological grading is the diagnostic standard for rejection, poor inter-pathologist agreement creates significant clinical uncertainty. The aim of this investigation is to demonstrate that cellular rejection grades generated via computational histological analysis are on-par with those provided by expert pathologists

Methods and results
The study cohort consisted of 2472 endomyocardial biopsy slides originating from three major US transplant centres. The ‘Computer-Assisted Cardiac Histologic Evaluation (CACHE)-Grader’ pipeline was trained using an interpretable, biologically inspired, ‘hand-crafted’ feature extraction approach. From a menu of 154 quantitative histological features relating the density and orientation of lymphocytes, myocytes, and stroma, a model was developed to reproduce the 4-grade clinical standard for cellular rejection diagnosis. CACHE-grader interpretations were compared with independent pathologists and the ‘grade of record’, testing for non-inferiority (δ = 6%). Study pathologists achieved a 60.7% agreement [95% confidence interval (CI): 55.2–66.0%] with the grade of record, and pair-wise agreement among all human graders was 61.5% (95% CI: 57.0–65.8%). The CACHE-Grader met the threshold for non-inferiority, achieving a 65.9% agreement (95% CI: 63.4–68.3%) with the grade of record and a 62.6% agreement (95% CI: 60.3–64.8%) with all human graders. The CACHE-Grader demonstrated nearly identical performance in internal and external validation sets (66.1% vs. 65.8%), resilience to inter-centre variations in tissue processing/digitization, and superior sensitivity for high-grade rejection (74.4% vs. 39.5%, P &lt; 0.001).

Conclusion
These results show that the CACHE-grader pipeline, derived using intuitive morphological features, can provide expert-quality rejection grading, performing within the range of inter-grader variability seen among human pathologists.
Driving following defibrillator implantation: a nationwide register-linked survey study
Authors: Bjerre Jenny , Rosenkranz Simone Hofman , Schou Morten , Jøns Christian , Philbert Berit Thornvig , Larroudé Charlotte , Nielsen Jens Cosedis , Johansen Jens Brock , Riahi Sam , Melchior Thomas Maria , Torp-Pedersen Christian , Hlatky Mark , Gislason Gunnar , Ruwald Anne-Christine 
Published: April 2021

Abstract

Aims
Patients are restricted from driving following implantable cardioverter defibrillator (ICD) implantation or shock. We sought to investigate how many patients are aware of, and adhere to, the driving restrictions, and what proportion experience an ICD shock or other cardiac symptoms while driving.

Methods and results
We performed a nationwide survey of all living Danish residents 18 years or older who received a first-time ICD between 2013 and 2016 (n = 3913) and linked their responses with nationwide registers. Of 2741 respondents (47% primary prevention, 83% male, median age 67 years), 2513 (92%) held a valid driver’s license at ICD implantation, 175 (7%) of whom had a license for professional driving. Many drivers were unaware of driving restrictions: primary prevention 58%; secondary prevention 36%; post-appropriate shock 28%; professional drivers 55%. Almost all (94%) resumed non-professional driving after ICD implantation, more than one-third during the restricted period; 35% resumed professional driving. During a median follow-up of 2.3 years, 5 (0.2%) reported receiving an ICD shock while driving, one of which resulted in a traffic accident. The estimated risk of harm was 0.0002% per person-year.

Conclusion
In this nationwide study, many ICD patients were unaware of driving restrictions, and more than one third resumed driving during a driving restriction period. However, the rate of reported ICD shocks while driving was very low.
Autonomic modulation and cardiac arrhythmias: old insights and novel strategies
Authors: Chatterjee Neal A , Singh Jagmeet P 
Published: April 2021

AbstractThe autonomic nervous system (ANS) plays a critical role in both health and states of cardiovascular disease. There has been a long-recognized role of the ANS in the pathogenesis of both atrial and ventricular arrhythmias (VAs). This historical understanding has been expanded in the context of evolving insights into the anatomy and physiology of the ANS, including dysfunction of the ANS in cardiovascular disease such as heart failure and myocardial infarction. An expanding armamentarium of therapeutic strategies—both invasive and non-invasive—have brought the potential of ANS modulation to contemporary clinical practice. Here, we summarize the integrative neuro-cardiac anatomy underlying the ANS, review the physiological rationale for autonomic modulation in atrial and VAs, highlight strategies for autonomic modulation, and finally frame future challenges and opportunities for ANS therapeutics.
Inhibitory effect of black cumin (Nigella sativa) seed essential oil on Fusobacterium nucleatum L-methionine-γ-lyase (L-methioninase) activity
Authors: Ishikawa Masao , Murata Takatoshi , Okamoto Masaaki , Miyanohara Mayu , Yamashita Mamiko , Hanada Nobuhiro , Senpuku Hidenobu , Shibuya Koji 
Published: April 2021

ABSTRACT
The enzyme L-methionine-γ-lyase is commonly found in a wide range of bacteria and catalyzes the α-elimination and γ-elimination of L-methionine to produce methyl mercaptan, α-ketobutyrate and ammonia. Black cumin seed essential oil (BC oil) reportedly exhibits deodorizing activity against methyl mercaptan. Therefore, we hypothesized that BC oil may also suppress methyl mercaptan production. In this study, we aimed to evaluate the inhibitory effect of BC oil on L-methionine-γ-lyase activity in Fusobacterium nucleatum. Recombinant L-methionine-γ-lyase was incubated under appropriate conditions with BC oil and its constituent thymoquinone. To analyze L-methionine-γ-lyase activity, α-ketobutyric acid and ammonia concentrations were determined. The concentrations of α-ketobutyric acid and ammonia were significantly decreased by 10 µg mL−1 of BC oil (P &lt; 0.01) and 16.4 µg/mL of thymoquinone (P &lt; 0.05). An enzyme kinetic assay showed a mixed inhibition pattern between L-methionine-γ-lyase and thymoquinone. In conclusion, BC oil not only had a deodorizing effect against methyl mercaptan but also an inhibitory effect on methyl mercaptan production through the suppression of L-methionine-γ-lyase activity. Thymoquinone may be mainly responsible for these effects of BC oil. Thus, application of natural BC oil may be adapted not only for medical use but also in other areas of life.
Grad-seq identifies KhpB as a global RNA-binding protein inClostridioides difficilethat regulates toxin production
Authors: Lamm-Schmidt Vanessa , Fuchs Manuela , Sulzer Johannes , Gerovac Milan , Hör Jens , Dersch Petra , Vogel Jörg , Faber Franziska 
Published: April 2021

ABSTRACTMuch of our current knowledge about cellular RNA–protein complexes in bacteria is derived from analyses in gram-negative model organisms, with the discovery of RNA-binding proteins (RBPs) generally lagging behind in Gram-positive species. Here, we have applied Grad-seq analysis of native RNA–protein complexes to a major Gram-positive human pathogen, Clostridioides difficile, whose RNA biology remains largely unexplored. Our analysis resolves in-gradient distributions for ∼88% of all annotated transcripts and ∼50% of all proteins, thereby providing a comprehensive resource for the discovery of RNA–protein and protein–protein complexes in C. difficile and related microbes. The sedimentation profiles together with pulldown approaches identify KhpB, previously identified in Streptococcus pneumoniae, as an uncharacterized, pervasive RBP in C. difficile. Global RIP-seq analysis establishes a large suite of mRNA and small RNA targets of KhpB, similar to the scope of the Hfq targetome in C. difficile. The KhpB-bound transcripts include several functionally related mRNAs encoding virulence-associated metabolic pathways and toxin A whose transcript levels are observed to be increased in a khpB deletion strain. Moreover, the production of toxin protein is also increased upon khpB deletion. In summary, this study expands our knowledge of cellular RNA protein interactions in C. difficile and supports the emerging view that KhpB homologues constitute a new class of globally acting RBPs in Gram-positive bacteria.
Using dedications to Charles VI to convey political messages: Honorat Bovet, Philippe de Mézières, Christine de Pizan and Pierre Salmon
Authors: Bourassa Kristin 
Published: April 2021

Abstract
The dedication of four French-language advice books to Charles VI of France (r. 1380–1422), two just after the king’s declaration of personal rule and two during the period dominated by his mental illness, was a strategic choice by the books’ authors. Honorat Bovet, Philippe de Mézières, Christine de Pizan and Pierre Salmon used these dedications to convey political messages not only to the king but also to his powerful male relatives. The dedications, the way the manuscripts represented Charles both textually and visually and the way the texts urged Charles’ relatives to support Charles and each other, all place the king at the centre of the political conversation. Casting both themselves and the king’s relatives as important contributors to French political life, the writers used the role of Charles as imagined reader of the books to urge his male relatives to prioritize the needs of king and kingdom above their own.
Modelling the impact of climate change on the occurrence of frost damage in Sitka spruce (Picea sitchensis) in Great Britain
Authors: Atucha-Zamkova A A , Steele K A , Smith A R 
Published: April 2021

Abstract
Climate change is predicted to increase temperature and seasonal temperature variance in Great Britain (GB). Sitka spruce (Picea sitchensis (Bong.) Carr) is the most important tree species used in commercial plantations throughout Europe and GB. Frosts that occur outside the winter dormancy period can negatively affect trees, since they happen after dehardening. Damage can be especially severe at bud burst, before emerging needles mature and form protective barriers. Here, we modelled the impact of climate change on frost sensitivity in Sitka spruce with temperature data from five climate projections. The UKCP09 climate model HadRm3 uses emission scenario SRESA1B for the years 2020–2099. The global and downscaled versions of the UKCP18 HadGem3 model use the emissions scenario RCP 8.5. The global model CMCC-CM uses the RCP 4.5 and RCP 8.5 emissions scenarios. The predictions based on these models were compared with results from gridded historical data for the period 1960–2015. Three indicators that assessed the frost sensitivity of Sitka spruce were explored: the total number of frosts between the onset of dehardening and the end of summer, which use three different temperature thresholds (Index 10°C, 1–3°C, 1–5°C); the total number of frosts after bud burst (Index 2); the number of days with minimum temperatures below the resistance level (backlashes) during the hardening–dehardening period (September–August) (Index 3). The indices were validated with historical data for frost damage across GB, and Index 1–3°C, Index 1–5°C and Index 3 were shown to be significantly correlated. The frequency of all frosts and backlashes is expected to decrease with climate change, especially under higher emissions scenarios. Post-bud burst frosts have been historically very rare in GB and remain so with climate change. Downscaled regional climate models detect geographic variability within GB and improve prediction of overall trends in frost damage in comparison to global climate change models for GB.
Multiplexing mutation rate assessment: determining pathogenicity of Msh2 variants in Saccharomyces cerevisiae
Authors: Ollodart Anja R , Yeh Chiann-Ling C , Miller Aaron W , Shirts Brian H , Gordon Adam S , Dunham Maitreya J 
Published: April 2021

Abstract
Despite the fundamental importance of mutation rate as a driving force in evolution and disease risk, common methods to assay mutation rate are time-consuming and tedious. Established methods such as fluctuation tests and mutation accumulation experiments are low-throughput and often require significant optimization to ensure accuracy. We established a new method to determine the mutation rate of many strains simultaneously by tracking mutation events in a chemostat continuous culture device and applying deep sequencing to link mutations to alleles of a DNA-repair gene. We applied this method to assay the mutation rate of hundreds of Saccharomyces cerevisiae strains carrying mutations in the gene encoding Msh2, a DNA repair enzyme in the mismatch repair pathway. Loss-of-function mutations in MSH2 are associated with hereditary nonpolyposis colorectal cancer, an inherited disorder that increases risk for many different cancers. However, the vast majority of MSH2 variants found in human populations have insufficient evidence to be classified as either pathogenic or benign. We first benchmarked our method against Luria–Delbrück fluctuation tests using a collection of published MSH2 missense variants. Our pooled screen successfully identified previously characterized nonfunctional alleles as high mutators. We then created an additional 185 human missense variants in the yeast ortholog, including both characterized and uncharacterized alleles curated from ClinVar and other clinical testing data. In a set of alleles of known pathogenicity, our assay recapitulated ClinVar’s classification; we then estimated pathogenicity for 157 variants classified as uncertain or conflicting reports of significance. This method is capable of studying the mutation rate of many microbial species and can be applied to problems ranging from the generation of high-fidelity polymerases to measuring the frequency of antibiotic resistance emergence.
Assessing Age-Friendly Community Progress: What Have We Learned?
Authors: Black Kathy , Oh Patricia 
Published: April 2021

Abstract

Background and Objectives
The Global Network of Age-Friendly Cities and Communities has grown steadily over the past decade across the United States. The age-friendly model calls for a 5-year process of continuous improvement across the stages of engagement, planning, action, and measurement, culminating in an evaluation of age-friendly progress. However, surprisingly, little is known regarding American age-friendly communities’ accomplishments to date.

Research Design and Methods
We utilized content analysis to assess the progress reported by American age-friendly communities (n = 30) that joined by end of year 2015 using the Age-Friendly Community Evidence-based Tool with expanded program evaluation measures including health equity as defined by the World Health Organization. We employed deductive analytic techniques to assess reported community performance in 11 thematic areas across the range of structures and processes that characterize age-friendly efforts.

Results
We found strong evidence in the areas of leadership and governance, harnessed resources, application of the age-friendly framework, and in multisector collaboration as well as reported provisions. All of the communities reported health equity aims, particularly in promoting accessible physical environments and social inclusion efforts. Our analysis further revealed relatively moderate evidence of older adult involvement and weak performance in the monitoring and reporting of evaluative findings as well as overall summation and dissemination plans.

Discussion and Implications
We conclude by synthesizing the overall performance reported by the age-friendly communities, highlighting both strengths and weaknesses. We also offer suggestions to enhance evaluative efforts and advance the dissemination of age-friendly community progress.
Higher-order Hamilton–Jacobi perturbation theory for anisotropic heterogeneous media: dynamic ray tracing in ray-centred coordinates
Authors: Iversen Einar , Ursin Bjørn , Saksala Teemu , Ilmavirta Joonas , de Hoop Maarten V 
Published: April 2021

SUMMARY
Dynamic ray tracing is a robust and efficient method for computation of amplitude and phase attributes of the high-frequency Green’s function. A formulation of dynamic ray tracing in Cartesian coordinates was recently extended to higher orders. Extrapolation of traveltime and geometrical spreading was demonstrated to yield significantly higher accuracy—for isotropic as well as anisotropic heterogeneous 3-D models of an elastic medium. This is of value in mapping, modelling and imaging, where kernel operations are based on extrapolation or interpolation of Green’s function attributes to densely sampled 3-D grids. We introduce higher-order dynamic ray tracing in ray-centred coordinates, which has certain advantages: (1) such coordinates fit naturally with wave propagation; (2) they lead to a reduction of the number of ordinary differential equations; (3) the initial conditions are simple and intuitive and (4) numerical errors due to redundancies are less likely to influence the computation of the Green’s function attributes. In a 3-D numerical example, we demonstrate that paraxial extrapolation based on higher-order dynamic ray tracing in ray-centred coordinates yields results highly consistent with those obtained using Cartesian coordinates. Furthermore, in a 2-D example we show that interpolation of dynamic ray tracing quantities along a wavefront can be done with much better consistency in ray-centred coordinates than in Cartesian coordinates. In both examples we measure consistency by means of constraints on the dynamic ray tracing quantities in the 3-D position space and in the 6-D phase space.
Extracting surface wave dispersion curves from asynchronous seismic stations: method and application
Authors: Rao Hao , Luo Yinhe , Zhao Kaifeng , Yang Yingjie 
Published: April 2021

SUMMARY
Correlation of the coda of Empirical Green's functions (EGFs) from ambient noise can be used to reconstruct EGFs between two seismic stations deployed different periods of time. However, such method requires a number of source stations deployed in the area surrounding a pair of asynchronous stations, which limit its applicability in cases where there are not so many available source stations. Here, we propose an alternative method, called two-station C2 method, which uses one single station as a virtual source to retrieve surface wave phase velocities between a pair of asynchronous stations. Using ambient noise data from USArray as an example, we obtain the interstation C2 functions using our C2 method and the traditional cross-correlation functions (C1 functions). We compare the differences between the C1 and C2 functions in waveforms, dispersion measurements, and phase velocity maps. Our results show that our C2 method can obtain reliable interstation phase velocity measurements, which can be used in tomography to obtain reliable phase velocity maps. Our method can significantly improve ray path coverage from asynchronous seismic arrays and enhance the resolution in ambient noise tomography for areas between asynchronous seismic arrays.
RNA kinase CLP1/Cbc regulates meiosis initiation in spermatogenesis
Authors: Wu Jianbo , Li Xin , Gao Zhiyang , Pang Lin , Liu Xian , Huang Xiahe , Wang Yingchun , Wang Zhaohui 
Published: April 2021

AbstractCLP1, TSEN complex, and VCP are evolutionarily conserved proteins whose mutations are associated with neurodegenerative diseases. In this study, we have found that they are also involved in germline differentiation. To optimize both quantity and quality in gametes production, germ cells expand themselves through limited mitotic cycles prior to meiosis. Stemming from our previous findings on the correlation between mRNA 3′-processing and meiosis entry, here we identify that the RNA kinase Cbc, the Drosophila member of the highly conserved CLP1 family, is a component of the program regulating the transition from mitosis to meiosis. Using genetic manipulations in Drosophila testis, we demonstrate that nuclear Cbc is required to promote meiosis entry. Combining biochemical and genetic methods, we reveal that Cbc physically and/or genetically intersects with Tsen54 and TER94 (VCP ortholog) in this process. The C-terminal half of Tsen54 is both necessary and sufficient for its binding with Cbc. Further, we illustrate the functional conservation between Cbc and mammalian CLP1 in the assays of subcellular localization and Drosophila fertility. As CLP1, TSEN complex, and VCP have also been identified in neurodegenerations of animal models, a mechanism involving these factors seems to be shared in gametogenesis and neurogenesis.
Vedolizumab Clinical Decision Support Tool Predicts Efficacy of Vedolizumab But Not Ustekinumab in Refractory Crohn’s Disease
Authors: Alric Hadrien , Amiot Aurélien , Kirchgesner Julien , Tréton Xavier , Allez Mathieu , Bouhnik Yoram , Beaugerie Laurent , Carbonnel Franck , Meyer Antoine 
Published: April 2021

AbstractIntroductionVedolizumab clinical decision support tool (VDZ-CDST) predicts response to vedolizumab, but whether this tool also predicts efficacy of other drugs in Crohn’s disease (CD) is unknown. This study aimed to assess the value of VDZ-CDST to predict vedolizumab and ustekinumab efficacy in patients with CD.Patients and methodsWe included consecutive CD patients refractory or intolerant to anti-TNF who started either vedolizumab or ustekinumab in 5 university hospitals between May 2014 and August 2018. The main end points were the rates of clinical remission and steroid-free clinical remission (SFCR) in each group of VDZ-CDST at week 48.ResultsOne hundred eighty patients were included; 94 received vedolizumab (VDZ-CDST ≤13: 32; VDZ-CDST &gt;13 and ≤19: 52; VDZ-CDST &gt;19: 10), and 86 received ustekinumab (VDZ-CDST ≤13: 16; VDZ-CDST &gt;13 and ≤19: 60; VDZ-CDST &gt;19: 10). At week 48 in the vedolizumab group, clinical remission and SFCR were reached in 9.4% with a VDZ-CDST ≤13, in 38.5% and 28.8% with a VDZ-CDST &gt;13 and ≤19, respectively, and in 80.0% with a VDZ-CDST &gt;19 (P &lt; 0.0001 and P &lt; 0.0001, respectively). In the ustekinumab cohort, clinical remission and SFCR were reached in 43.8% and 37.5% with a VDZ-CDST ≤13, in 55.0% and 50.0% with a VDZ-CDST &gt;13 and ≤19, and 50.0% with a VDZ-CDST &gt;19, respectively (P = 0.65 and P = 0.46, respectively). VDZ-CDST identified SFCR with an area under the curve of 0.69 (95% CI, 0.57–0.82) for vedolizumab and 0.52 (95% CI, 0.40–0.65) for ustekinumab.ConclusionThe VDZ-CDST predicts clinical remission and SFCR at week 48 for vedolizumab but not for ustekinumab in CD patients refractory or intolerant to anti-TNF.
Glucocentric Metabolism in Ultra-Endurance Sled Dogs
Authors: Davis Michael S 
Published: April 2021

AbstractThe total energy expenditure of a racing sled dog can exceed 500 kcal/kg bodyweight during typical events spanning a week or more. Based on early research, as well as practical considerations, modern commercial diets are formulated to meet these energy requirements using fat and protein. However, more recent research provides a clear picture of a canine athlete with glucocentric metabolism, including many conditioning-induced adaptations oriented toward sustaining submaximal exercise with glucose as the primary metabolic fuel despite the consumption of fat as the primary dietary energy source. The specific strategies used by racing sled dogs to maintain a robust supply of glucose during exercise, as well as the possible role of fat in facilitating that metabolic priority, is the subject of ongoing research.