bluuebunny/crossref_metadata_2025_split huggingface dataset:
Benchmarking Combinations of Learning and Testing Algorithms for Automata Learning
Authors: Aichernig Bernhard K. , Tappler Martin , Wallner Felix 
Published: June 2023

Automata learning enables model-based analysis of black-box systems by automatically constructing models from system observations, which are often collected via testing. The required testing budget to learn adequate models heavily depends on the applied learning and testing techniques.
Test cases executed for learning (1) collect behavioural information and (2) falsify learned hypothesis automata. Falsification test-cases are commonly selected through conformance testing. Active learning algorithms additionally implement test-case selection strategies to gain information, whereas passive algorithms derive models solely from given data. In an active setting, such algorithms require external test-case selection, like repeated conformance testing to extend the available data.
There exist various approaches to learning and conformance testing, where interdependencies among them affect performance. We investigate the performance of combinations of six learning algorithms, including a passive algorithm, and seven testing algorithms by performing experiments using 153 benchmark models. We discuss insights regarding the performance of different configurations for various types of systems. Our findings may provide guidance for future users of automata learning. For example, counterexample processing during learning strongly impacts efficiency, which is further affected by testing approach and system type. Testing with the random Wp-method performs best overall, while mutation-based testing performs well on smaller models.
Relationship between ABO Blood Group Alleles and Pancreatic Cancer Is Modulated by Secretor (FUT2) Genotype, but Not Lewis Antigen (FUT3) Genotype
Authors: Kim Jihye , Yuan Chen , Amundadottir Laufey T. , Wolpin Brian M. ,   for the Pancreatic Cancer Cohort Consortium (PanScan), Klein Alison P. ,   for the Pancreatic Cancer Case–Control Consortium (PanC4), Risch Harvey A. , Kraft Peter 
Published: June 2023

Abstract

Background:
In Western populations, pancreatic ductal adenocarcinoma (PDAC) risk has been found to be greater among individuals with non-O blood types than those with O blood type. However, the association has not been fully evaluated with respect to FUT2 (determining secretor status) and FUT3 (determining Lewis antigens) status, two biologically important genes in the expression of ABO blood groups with PDAC.

Methods:
We examined interactions in data from 8,027 cases and 11,362 controls in large pancreatic cancer consortia (PanScan I-III and PanC4) by using genetic variants to predict ABO blood groups (rs505922 and rs8176746), secretor status (rs601338), and Lewis antigens (rs812936, rs28362459, and rs3894326). Multivariable logistic regression was used to estimate ORs and 95% confidence intervals (CI) of the risk of PDAC adjusted for age and sex. We examined multiplicative interactions of ABO with secretor status and Lewis antigens by considering each product term between ABO and secretor and between ABO and Lewis antigens individually.

Results:
We found that the increased risk associated with non-O blood groups was somewhat stronger among secretors than nonsecretors [ORs, 1.28 (95% CI, 1.15–1.42) and 1.17 (95% CI, 1.03–1.32) respectively; Pinteraction = 0.002]. We did not find any interactions between ABO and Lewis antigens.

Conclusions:
Our large consortia data provide evidence of effect modification in the association between non-O blood type and pancreatic cancer risk by secretor status.

Impact:
Our results indicate that the association between ABO blood type and PDAC risk may vary by secretor status, but not by Lewis antigens.
Functional Exploration of Conserved Sequences in the Distal Face of Angiotensinogen—Brief Report
Authors: Amioka Naofumi , Wu Chia-Hua , Sawada Hisashi , Ito Sohei , Pettey Alex C. , Wu Congqing , Moorleghen Jessica J. , Howatt Deborah A. , Graf Gregory A. , Vander Kooi Craig W. , Daugherty Alan , Lu Hong S. 
Published: June 2023

BACKGROUND:
Angiotensinogen (AGT) is an essential component in the renin-angiotensin system. AGT has highly conserved sequences in the loop and β-sheet regions among species; however, their functions have not been studied.

METHODS:

Adeno-associated viral vector (AAV) serotype 2/8 encoding mouse AGT with mutations of conserved sequences in the loop (AAV.loop-Mut), β-sheet (AAV.βsheet-Mut), or both regions (AAV.loop/βsheet-Mut) was injected into male hepatocyte-specific AGT-deficient (hepAGT
−/−
) mice in an LDL (low-density lipoprotein) receptor–deficient background. AAV containing mouse wild-type AGT (AAV.mAGT) or a null vector (AAV.null) were used as controls. Two weeks after AAV administration, all mice were fed a western diet for 12 weeks. To determine how AGT secretion is regulated in hepatocytes, AAVs containing the above mutations were transducted into HepG2 cells.

RESULTS:

In hepAGT
−/−
mice infected with AAV.loop-Mut or βsheet-Mut, plasma AGT concentrations, systolic blood pressure, and atherosclerosis were comparable to those in AAV.mAGT-infected mice. Interestingly, plasma AGT concentrations, systolic blood pressure, and atherosclerotic lesion size in hepAGT
−/−
mice infected with AAV.loop/βsheet-Mut were not different from mice infected with AAV.null. In contrast, hepatic
Agt
mRNA abundance was elevated to a comparable magnitude as AAV.mAGT-infected mice. Immunostaining showed that AGT protein was accumulated in hepatocytes of mice infected with AAV.loop/βsheet-Mut or HepG2 cells transducted with AAV.loop/βsheet-Mut. Accumulated AGT was not located in the endoplasmic reticulum.

CONCLUSIONS:
The conserved sequences in either the loop or β-sheet region individually have no effect on AGT regulation, but the conserved sequences in both regions synergistically contribute to the secretion of AGT from hepatocytes.
Dedifferentiation and Proliferation of Artery Endothelial Cells Drive Coronary Collateral Development in Mice
Authors: Arolkar Gauri , Kumar Sneha K. , Wang Hanjay , Gonzalez Karen M. , Kumar Suraj , Bishnoi Bhavnesh , Rios Coronado Pamela E. , Woo Y. Joseph , Red-Horse Kristy , Das Soumyashree 
Published: June 2023

Background:
Collateral arteries act as natural bypasses which reroute blood flow to ischemic regions and facilitate tissue regeneration. In an injured heart, neonatal artery endothelial cells orchestrate a systematic series of cellular events, which includes their outward migration, proliferation, and coalescence into fully functional collateral arteries. This process, called artery reassembly, aids complete cardiac regeneration in neonatal hearts but is absent in adults. The reason for this age-dependent disparity in artery cell response is completely unknown. In this study, we investigated if regenerative potential of coronary arteries is dictated by their ability to dedifferentiate.

Methods:
Single-cell RNA sequencing of coronary endothelial cells was performed to identify differences in molecular profiles of neonatal and adult endothelial cells in mice. Findings from this in silico analyses were confirmed with in vivo experiments using genetic lineage tracing, whole organ immunostaining, confocal imaging, and cardiac functional assays in mice.

Results:
Upon coronary occlusion, neonates showed a significant increase in actively cycling artery cells and expressed prominent dedifferentiation markers. Data from in silico pathway analyses and in vivo experiments suggested that upon myocardial infarction, cell cycle reentry of preexisting neonatal artery cells, the subsequent collateral artery formation, and recovery of cardiac function are dependent on arterial VegfR2 (vascular endothelial growth factor receptor-2). This subpopulation of dedifferentiated and proliferating artery cells was absent in nonregenerative postnatal day 7 or adult hearts.

Conclusions:
These data indicate that adult artery endothelial cells fail to drive collateral artery development due to their limited ability to dedifferentiate and proliferate.
Outcomes With Peripheral Venoarterial Extracorporeal Membrane Oxygenation for Suspected Acute Myocarditis: 10-Year Experience From the Extracorporeal Life Support Organization Registry
Authors: Nunez Jose I. , Grandin E. Wilson , Reyes-Castro Tiago , Sabe Marwa , Quintero Pablo , Motiwala Shweta , Fleming Lisa M. , Sriwattanakomen Roy , Ho Jennifer E. , Kennedy Kevin , Tonna Joseph E. , Garan A. Reshad 
Published: June 2023

BACKGROUND:
Acute myocarditis can result in severe hemodynamic compromise requiring venoarterial extracorporeal membrane oxygenation (VA-ECMO). Outcomes and factors associated with mortality among myocarditis patients are not well described in the modern ECMO era.

METHODS:
We queried the Extracorporeal Life Support Organization registry from 2011 to 2020 for adults with suspected acute myocarditis undergoing peripheral VA-ECMO support. The primary outcome was in-hospital mortality and was compared to all-comers receiving VA-ECMO in the registry over the same period. Secondary outcomes were rates of bridging to advanced therapies and ECMO complications. We used multivariable logistic regression to examine factors associated with in-hospital mortality.

RESULTS:

Among 850 patients with suspected acute myocarditis receiving peripheral VA-ECMO, the mean age was 41 years, 52% were men, 39% Asian race, and 14.8% underwent extracorporeal cardiopulmonary resuscitation. During the study period, in-hospital mortality steadily declined and was 58.3% for all all-comers receiving VA-ECMO compared with 34.9% for patients with myocarditis (
P
<0.001). After multivariable modeling, risk factors for mortality were earlier year of support, older age, higher weight, Asian race, need for extracorporeal cardiopulmonary resuscitation, sepsis, and lower mean arterial pressure and pH prior to ECMO initiation. ECMO complications including bleeding, limb ischemia, infections and ischemic stroke were more common among nonsurvivors and significantly declined during the study period.

CONCLUSIONS:
Compared with all-comers supported with VA-ECMO, in-hospital mortality for patients with acute myocarditis is significantly lower, with nearly two-thirds of patients surviving to discharge. Major modifiable risk factors for mortality were ongoing cardiopulmonary resuscitation requiring ECMO and markers of illness severity prior to ECMO.
Trends in Short‐, Intermediate‐, and Long‐Term Mortality Following Hospitalization for Myocardial Infarction Among Medicare Beneficiaries, 2008 to 2018
Authors: Kini Vinay , Magid David J. , Luo Qian , Masoudi Frederick A. , Black Bernard , Moghtaderi Ali 
Published: June 2023

Background
Advances in technology and care quality have transformed the care of acute myocardial infarction (AMI), but little is known about trends in mortality rates across separate time periods after hospitalization.

Methods and Results
We identified all Medicare fee‐for‐service beneficiaries hospitalized with incident AMI from 2008 to 2018. We calculated unadjusted mortality rates by dividing the number of all‐cause deaths by the number of patients with incident AMI for the following time periods: acute (in hospital), post acute (0–30 days after hospital discharge), short term (31 days to 1 year after discharge), intermediate term (1–2 years after discharge), and long term (2–3 years after discharge). Each period was considered separately (ie, patients who died during one period were not counted in subsequent periods). Using logistic regression to account for differences in patient characteristics, we calculated annual risk standardized mortality ratios defined as observed over expected mortality based on 2008 rates. Among 768 084 patients with incident AMI (mean age 81 years, 48% male, 87% White), declines in observed‐to‐expected mortality ratios were observed for each time period: acute (0.68 [95% CI, 0.66–0.71]), postacute (0.72 [95% CI, 0.71–0.75]), short term (0.77 [95% CI, 0.75–0.78]), intermediate term (0.79 [95% CI, 0.77–0.81]), and long term (0.77 [95% CI, 0.75–0.79]). Declines were observed both for patients with and without ST‐segment–elevation AMI.

Conclusions
For patients with incident AMI, there have been improvements in mortality rates across periods spanning the hospital stay through 3 years after discharge, reflecting advances in AMI care from hospitalization through long‐term outpatient follow‐up.
Interleukin‐1β Disruption Protects Male Mice From Heart Failure With Preserved Ejection Fraction Pathogenesis
Authors: Srinivas Balaji K. , Bourdi Aya , O'Regan Jacob D. , Malavalli Kumar D. , Rhaleb Nour‐Eddine , Belmadani Souad , Matrougui Khalid 
Published: June 2023

Background
Heart failure with preserved ejection fraction (HFpEF) is a significant unmet need in cardiovascular medicine and remains an untreatable cardiovascular disease. The role and mechanism of interleukin‐1β in HFpEF pathogenesis are poorly understood.

Methods and Results

C57/Bl6J and interleukin‐1β
−/−
male mice were randomly divided into 4 groups. Groups 1 and 2: C57/Bl6J and interleukin‐1β
−/−
mice were fed a regular diet for 4 months and considered controls. Groups 3 and 4: C57/Bl6 and interleukin‐1β
−/−
mice were fed a high‐fat diet with N[w]‐nitro‐l‐arginine methyl ester (endothelial nitric oxide synthase inhibitor, 0.5 g/L) in the drinking water for 4 months. We measured body weight, blood pressure, diabetes status, cardiac function/hypertrophy/inflammation, fibrosis, vascular endothelial function, and signaling. C57/Bl6 fed a high‐fat diet and N[w]‐nitro‐l‐arginine methyl ester in the drinking water for 4 months developed HFpEF pathogenesis characterized by obesity, diabetes, hypertension, cardiac hypertrophy, lung edema, low running performance, macrovascular and microvascular endothelial dysfunction, and diastolic cardiac dysfunction but no change in cardiac ejection fraction compared with control mice. Interestingly, the genetic disruption of interleukin‐1β protected mice from HFpEF pathogenesis through the modulation of the inflammation and endoplasmic reticulum stress mechanisms.

Conclusions
Our data suggest that interleukin‐1β is a critical driver in the development of HFpEF pathogenesis, likely through regulating inflammation and endoplasmic reticulum stress pathways. Our findings provide a potential therapeutic target for HFpEF treatment.
Sex Differences in Murray Law‐Based Quantitative Flow Ratio Among Patients With Intermediate Coronary Lesions
Authors: Zuo Wenjie , Sun Renhua , Ji Zhenjun , Zuo Pengfei , Zhang Xiaoguo , Huang Rong , Tao Zaixiao , Tu Shengxian , Li Yongjun , Ma Genshan 
Published: June 2023

Background
The Murray law‐based quantitative flow ratio (μQFR) is a novel technique that simulates fractional flow reserve (FFR) from a single angiographic view. However, the impact of sex differences on the diagnostic performance of μQFR has not been investigated.

Methods and Results

In this study, FFR and μQFR were assessed in 497 intermediate stenoses (30%–70% by visual estimation) from 460 patients (34.3% female). Physiological significance was defined as FFR ≤0.80 or μQFR ≤0.80. After adjusting for potential confounders, female sex was independently associated with higher FFR (
P
=0.048 and 0.026, respectively) and μQFR (
P
=0.001 for both) in both fully adjusted and stepwise backward models. μQFR provided superior diagnostic accuracy compared with angiography alone for detecting FFR ≤0.80 in both women (area under the curve, 0.93 [95% CI, 0.88–0.97] versus 0.80 [95% CI, 0.73–0.86];
P
=0.001) and men (area under the curve, 0.88 [95% CI, 0.84–0.92] versus 0.73 [95% CI, 0.68–0.78];
P
<0.001), with comparable performance between the sexes (
P
=0.175). In the multivariable analysis, sex was not a significant factor contributing to the overall disagreement between FFR and μQFR.

Conclusions
Regardless of angiographic stenosis severity, women tend to have higher FFR and μQFR values than men. Furthermore, μQFR performs similarly well in both sexes and offers improved diagnostic accuracy over angiography alone, indicating its potential as a reliable, wire‐free tool to identify functional ischemia.
Metabolic Signatures of Cardiac Dysfunction, Multimorbidity, and Post–Transcatheter Aortic Valve Implantation Death
Authors: Perry Andrew S. , Zhao Shilin , Murthy Venkatesh , Gupta Deepak K. , Fearon William F. , Kim Juyong B. , Kapadia Samir , Kumbhani Dharam J. , Gillam Linda , Whisenant Brian , Quader Nishath , Zajarias Alan , Mallugari Ravinder R. , Clark Daniel E. , Patel Jay N. , Gonzales Holly , Welt Frederick G. , Bavry Anthony A. , Coylewright Megan , Piana Robert N. , Vatterott Anna , Jackson Natalie , Gerszten Robert E. , Lindman Brian R. , Shah Ravi , Elmariah Sammy 
Published: June 2023

Background
Studies in mice and small patient subsets implicate metabolic dysfunction in cardiac remodeling in aortic stenosis, but no large comprehensive studies of human metabolism in aortic stenosis with long‐term follow‐up and characterization currently exist.

Methods and Results

Within a multicenter prospective cohort study, we used principal components analysis to summarize 12 echocardiographic measures of left ventricular structure and function pre–transcatheter aortic valve implantation in 519 subjects (derivation). We used least absolute shrinkage and selection operator regression across 221 metabolites to define metabolic signatures for each structural pattern and measured their relation to death and multimorbidity in the original cohort and up to 2 validation cohorts (N=543 for overall validation). In the derivation cohort (519 individuals; median age, 84 years, 45% women, 95% White individuals), we identified 3 axes of left ventricular remodeling, broadly specifying systolic function, diastolic function, and chamber volumes. Metabolite signatures of each axis specified both known and novel pathways in hypertrophy and cardiac dysfunction. Over a median of 3.1 years (205 deaths), a metabolite score for diastolic function was independently associated with post–transcatheter aortic valve implantation death (adjusted hazard ratio per 1 SD increase in score, 1.54 [95% CI, 1.25–1.90];
P
<0.001), with similar effects in each validation cohort. This metabolite score of diastolic function was simultaneously associated with measures of multimorbidity, suggesting a metabolic link between cardiac and noncardiac state in aortic stenosis.

Conclusions
Metabolite profiles of cardiac structure identify individuals at high risk for death following transcatheter aortic valve implantation and concurrent multimorbidity. These results call for efforts to address potentially reversible metabolic biology associated with risk to optimize post–transcatheter aortic valve implantation recovery, rehabilitation, and survival.
Virtue Discounting: Observability Reduces Moral Actors’ Perceived Virtue
Authors: Kraft-Todd Gordon T. , Kleiman-Weiner Max , Young Liane 
Published: June 2023

Abstract
Performing prosociality in public presents a paradox: only by doing so can people demonstrate their virtue and also influence others through their example, yet observers may derogate actors’ behavior as mere “virtue signaling.” Here we investigate the role of observability of actors’ behavior as one reason that people engage in such “virtue discounting.” Further, we investigate observers’ motivational inferences as a mechanism of this effect, using the comparison of generosity and fairness as a case study among virtues. Across 14 studies (7 preregistered, total N = 9,360), we show that public actors are perceived as less virtuous than private actors, and that this effect is stronger for generosity compared to fairness (i.e., differential virtue discounting). Exploratory factor analysis suggests that three types of motives—principled, reputation-signaling, and norm-signaling—affect virtue discounting. Using structural equation modeling, we show that observability’s effect on actors’ trait virtue ratings is largely explained by inferences that actors have less principled motivations. Further, we leverage experimental evidence to provide stronger causal evidence of these effects. We discuss theoretical and practical implications of our findings, as well as future directions for research on the social perception of virtue.
The Eye Stays in the Picture: Virtual Images in Early Modern and Modern Optics
Authors: Borrelli Arianna 
Published: June 2023

Abstract
In optics, real images can be projected onto a screen, while virtual ones always remain behind mirrors. This apparently straightforward distinction is based on complex premises which emerged in the Early Modern period, and its development went hand in hand with a transformation of the notion of image, which became detached from sensual perception. In this article I will outline this historical process, and argue that the distinction between a real and virtual image still implies a reference to visual perception which makes it problematic, yet useful for didactic purposes.
Virtuality in Modern Physics in the 1920s and 1930s: Meaning(s) of an Emerging Notion
Authors: Martinez Jean-Philippe 
Published: June 2023

Abstract
This article discusses the meaning of the notion of virtuality in modern physics. To this end, it develops considerations on the introduction and establishment in nuclear physics of two independent concepts at the turn of the 1920s and 1930s: that of the virtual state, used in the context of neutron scattering studies, and that of the virtual transition, useful for the theoretical understanding of strong nuclear forces, which forms the basis of what are now called virtual particles. Their comparative analysis highlights the theoretical nature of virtual entities and processes in modern physics. It also shows how the virtual has been associated with various purely physical attributes, leading to a form of polysemy of the term, from the beginning of the application of these concepts.
Understanding, Virtually: How Does the Synthetic Cell Matter?
Authors: Broeks Daphne , Knuuttila Tarja , de Regt Henk 
Published: June 2023

Abstract
This paper examines how scientific understanding is enhanced by virtual entities, focusing on the case of the synthetic cell. Comparing it to other virtual entities and environments in science, we argue that the synthetic cell has a virtual dimension, in that it is functionally similar to living cells, though it does not mimic any particular naturally evolved cell (nor is it constructed to do so). In being cell-like at most, the synthetic cell is akin to many other virtual objects as it is selective and only partially implemented. However, there is one important difference: it is constructed by using the same materials and, to some extent, the same kind of processes as its natural counterparts. In contrast to virtual reality, especially to that of digital entities and environments, the details of its implementation is what matters for the scientific understanding generated by the synthetic cell. We conclude by arguing for the close connection between the virtual and the artifactual.