bluuebunny/crossref_metadata_2025 huggingface dataset:
Is act-consequentialism self-effacing?
Authors: Venkatesh Nikhil
Published: July 2021

Act-consequentialism (C) is self-effacing for an agent iff that agent’s not accepting C would produce the best outcome. The question of whether C is self-effacing is important for evaluating C. Some hold that if C is self-effacing that would be a mark against it (Williams 1973: 134); however, the claim that C is self-effacing is also used to defend C against certain objections (Parfit 1984: Ch. 1, Railton 1984).

In this paper I will show that one argument suggested by Parfit and Railton fails to establish that C is self-effacing for individuals. However, a slightly different argument may show that C is self-effacing for groups. This raises the intriguing possibility that it might be right for an individual, but not for a group of which they are a member, to accept a moral theory. This possibility, odd though it seems, might be helpful to consequentialists.
A systematic evaluation of the computational tools for lncRNA identification
Authors: Zheng Hansi , Talukder Amlan , Li Xiaoman , Hu Haiyan
Published: July 2021

The computational identification of long non-coding RNAs (lncRNAs) is important to study lncRNAs and their functions. Despite the existence of many computation tools for lncRNA identification, to our knowledge, there is no systematic evaluation of these tools on common datasets and no consensus regarding their performance and the importance of the features used. To fill this gap, in this study, we assessed the performance of 17 tools on several common datasets. We also investigated the importance of the features used by the tools. We found that the deep learning-based tools have the best performance in terms of identifying lncRNAs, and the peptide features do not contribute much to the tool accuracy. Moreover, when the transcripts in a cell type were considered, the performance of all tools significantly dropped, and the deep learning-based tools were no longer as good as other tools. Our study will serve as an excellent starting point for selecting tools and features for lncRNA identification.
GPR151 in nociceptors modulates neuropathic pain via regulating P2X3 function and microglial activation
Authors: Xia Li-Ping , Luo Hao , Ma Qiang , Xie Ya-Kai , Li Wei , Hu Hailan , Xu Zhen-Zhong
Published: July 2021

Neuropathic pain is a major health problem that affects up to 7–10% of the population worldwide. Currently, neuropathic pain is difficult to treat because of its elusive mechanisms.

Here we report that orphan G protein-coupled receptor 151 (GPR151) in nociceptive sensory neurons controls neuropathic pain induced by nerve injury. GPR151 was mainly expressed in non-peptidergic C-fibre dorsal root ganglion neurons and highly upregulated after nerve injury. Importantly, conditional knockout of Gpr151 in adult nociceptive sensory neurons significantly alleviated chronic constriction injury-induced neuropathic pain-like behaviour but did not affect basal nociception. Moreover, GPR151 in DRG neurons was required for chronic constriction injury-induced neuronal hyperexcitability and upregulation of colony-stimulating factor 1 (CSF1), which is necessary for microglial activation in the spinal cord after nerve injury. Mechanistically, GPR151 coupled with P2X3 ion channels and promoted their functional activities in neuropathic pain-like hypersensitivity. Knockout of Gpr151 suppressed P2X3-mediated calcium elevation and spontaneous pain behaviour in chronic constriction injury mice. Conversely, overexpression of Gpr151 significantly enhanced P2X3-mediated calcium elevation and dorsal root ganglion neuronal excitability. Furthermore, knockdown of P2X3 in dorsal root ganglia reversed chronic constriction injury-induced CSF1 upregulation, spinal microglial activation and neuropathic pain-like behaviour. Finally, the coexpression of GPR151 and P2X3 was confirmed in small-diameter human dorsal root ganglion neurons, indicating the clinical relevance of our findings.

Together, our results indicate that GPR151 in nociceptive dorsal root ganglion neurons plays a key role in the pathogenesis of neuropathic pain and could be a potential target for treating neuropathic pain.
Christian Bioethics and the Partisan Commitments of Secular Bioethicists: Epistemic Injustice, Moral Distress, Civil Disobedience
Authors: Cherry Mark J
Published: July 2021

Secular bioethicists do not speak from a place of distinction, but from within particular culturally, socially, and historically conditioned standpoints. As partisans of moral and ideological agendas, they bring their own biases, prejudices, and worldviews to their roles as ethical consultants, social advocates, and academics, attempting rhetorically to sway others and shift policy to a preferred point of view. Their pronouncements represent just one voice among others, even when delivered with strident rhetoric, in an educated and knowing tone, from within institutional positions of power. This essay argues that, given the hegemony of progressive secular bioethics, traditional Christians routinely face epistemic injustice within medicine. That is, Christian knowledge regarding moral reality is all too often demeaned or dismissed, unless such norms can be translated into and defended within a secular ethos. Given such systemic bias, I argue, Christians also experience significant moral distress: they are fully aware of their moral obligations and what they ought to do, but institutionalized power structures make it nearly impossible to so act. But, Christian physicians are not mere technicians, obliged to provide whatever patients request from the list of legally available treatments. That antireligious critics seek to remove the rights of Christian physicians to limit how they practice medicine, where they do not offer or refer for abortion, euthanasia, physician-assisted suicide, and other inappropriate forms of care, is unjustified and prejudicial, singling out Christians, and other religious groups, for singular treatment. Regardless of what the law requires or institutional policy demands, however, Christians are obliged to submit to God in all things. As a result, they may at times find themselves required to engage in acts of civil disobedience.
On the relevance of Knight, Keynes and Shackle for unawareness research
Authors: Svetlova Ekaterina
Published: July 2021

This paper is dedicated to the interpretation of Knightian and Keynesian uncertainty as a situation of unawareness in which agents lack perfect knowledge of possible future states (not just of probabilities assigned to those states). So far, a systematic and nuanced debate of unawareness with relation to Knight’s and Keynes’ legacy has been largely neglected. The paper aims to fill this gap. It discusses in detail how Knight’s, Keynes’ and also Shackle’s ideas about the state space, surprises and ignorance are echoed (but often unacknowledged) in contemporary unawareness research. Parallel reading of these two streams of the literature reveals strong commonalities in argumentation, suggesting that the topic of unawareness could facilitate the dialogue between Post-Keynesians and mainstream economics. The paper concludes with a list of research questions relevant to the development of such a dialogue.
Juvenile moose stress and nutrition dynamics related to winter ticks, landscape characteristics, climate-mediated factors and survival
Authors: Rosenblatt Elias , DeBow Jacob , Blouin Joshua , Donovan Therese , Murdoch James , Creel Scott , Rogers Will , Gieder Katherina , Fortin Nick , Alexander Cedric
Published: July 2021

Moose populations in the northeastern United States have declined over the past 15 years, primarily due to the impacts of winter ticks. Research efforts have focused on the effects of winter tick infestation on moose survival and reproduction, but stress and nutritional responses to ticks and other stressors remain understudied. We examined the influence of several environmental factors on moose calf stress hormone metabolite concentrations and nutritional restriction in Vermont, USA. We collected 407 fecal and 461 snow urine samples from 84 radio-collared moose calves in the winters of 2017–2019 (January–April) to measure fecal glucocorticoid metabolites (fGCM) concentrations and urea nitrogen:creatinine (UN:C) ratios. We used generalized mixed-effects models to evaluate the influence of individual condition, winter ticks, habitat, climate and human development on stress and nutrition in calf moose. We then used these physiological data to build generalized linear models to predict calf winter survival. Calf fGCM concentrations increased with nutritional restriction and snow depth during adult winter tick engorgement. Calf UN:C ratios increased in calves with lighter weights and higher tick loads in early winter. Calf UN:C ratios also increased in individuals with home ranges composed of little deciduous forests during adult winter tick engorgement. Our predictive models estimated that winter survival was negatively related to UN:C ratios and positively related to fGCM concentrations, particularly in early winter. By late March, as winter ticks are having their greatest toll and endogenous resources become depleted, we estimated a curvilinear relationship between fGCM concentrations and survival. Our results provide novel evidence linking moose calf stress and nutrition, a problematic parasite and challenging environment and winter survival. Our findings provide a baseline to support the development of non-invasive physiological monitoring for assessing environmental impacts on moose populations.
Prognostic impact of left ventricular ejection fraction recovery in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: analysis of an 11-year all-comers registry
Authors: Otero-García Oscar , Cid-Álvarez Ana Belén , Juskova Mària , Álvarez-Álvarez Belén , Tasende-Rey Pablo , Gude-Sampedro Francisco , García-Acuña José María , Agra-Bermejo Rosa , López-Otero Diego , Sanmartín-Pena Juan Carlos , Martínez-Monzonís Amparo , Trillo-Nouche Ramiro , González-Juanatey José R
Published: July 2021

Aims

Left ventricular ejection fraction (LVEF) recovery after an ST-segment elevation myocardial infarction (STEMI) identifies a group of patients with a better prognosis. However, the association between long-term outcomes and LVEF recovery among patients with STEMI undergoing primary percutaneous coronary intervention (PCI) has not yet been well investigated. Our study aims to detect differences in long-term all-cause and cardiovascular mortality between patients who recover LVEF at 1-year post-PCI and those who do not, and search for predictors of LVEF recovery.

Methods and results

This is a retrospective, single-centre study of 2170 consecutive patients admitted for STEMI in which primary PCI is performed. LVEF was determined at admission and at 1-year follow-up. The primary outcomes were long-term all-cause and cardiovascular mortality. Among the 2168 patients with baseline LVEF data, 822 (38%) had a LVEF < 50% and 1346 (62%) ≥ 50%. Among those with LVEF < 50%, LVEF data at 1-year were available in 554, and 299 (54.0%) presented with complete recovery (LVEF ≥ 50%). LVEF recovery was associated with a reduction in long-term all-cause and cardiovascular mortality (P < 0.0001). Female sex, treatment with ACEIs, lower creatinine levels, infarct-related artery different from the left main or left anterior descendent artery, and absence of prior ischaemic heart disease were independently associated with LVEF recovery.

Conclusions

Nearly 40% of patients with STEMI undergoing primary PCI presented with LVEF depression at hospital admission. Among them, LVEF recovery at 1-year occurred in more than 50% and was independently associated with a significant decrease in long-term all-cause and cardiovascular mortality.
Case report of Barth syndrome: a forgotten cause of cardiomyopathy
Authors: Rao Shiavax , Kanwal Arjun , Padmanabhan Sriram
Published: July 2021

Background

Barth syndrome (BTHS) is a rare X-linked recessive disorder characterized by clinical features including cardiomyopathy, skeletal myopathy, neutropenia, growth delay, and exercise intolerance. It is often considered to be a paediatric disease, owing to most cases being diagnosed during childhood and mortality being the highest during the first few years of life.

Case summary

We report a case of dilated cardiomyopathy due to BTHS in a 27-year-old adult male patient, who initially presented with lightheadedness, dyspnoea, orthopnoea, and bilateral lower extremity oedema. Key findings from investigations included leukopenia, prolonged QTc interval, reduced left ventricular ejection fraction (LVEF), global enlargement of all heart chambers, patent coronary arteries, and mild pulmonary hypertension. The patient was diuresed to euvolemia and discharged with a LifeVest. Guideline-directed medical therapy was initiated and uptitrated as an outpatient. A repeat echocardiogram 2 years after initial presentation showed marked improvement in LVEF.

Discussion

It is possible that there are adult patients with idiopathic cardiomyopathy, which may be attributable to BTHS. In the absence of an obvious underlying cause, with the appropriate historical information, clinical exam, laboratory investigations, and imaging findings, BTHS should be considered as a likely cause of non-ischaemic cardiomyopathy.
Cost-effectiveness analysis of screening for first-degree relatives of patients with bicuspid aortic valve
Authors: Tessler Idit , Leshno Moshe , Shmueli Amir , Shpitzen Shoshana , Durst Ronen , Gilon Dan
Published: July 2021

Aims

Bicuspid aortic valve (BAV) is the commonest congenital heart valve malformation, and is associated with life-threatening complications. Given the high heritability index of BAV, many experts recommend echocardiography screening for first-degree relatives (FDRs) of an index case. Here, we aim to evaluate the cost-effectiveness of such cascade screening for BAV.

Methods and results

Using a decision-analytic model, we performed a cost-effectiveness analysis of echocardiographic screening for FDRs of a BAV index case. Data on BAV probabilities and complications among FDRs were derived from our institution's BAV familial cohort and from the literature on population-based BAV cohorts with long-term follow-up. Health gain was measured as quality-adjusted life years (QALYs). Cost inputs were based on list prices and literature data. One-way and probabilistic sensitivity analyses were performed to account for uncertainty in the model's variables. Screening of FDRs was found to be the dominant strategy, being more effective and less costly than no screening, with savings of €644 and gains of 0.3 QALY. Results were sensitive throughout the range of the main model's variables, including the full range of reported BAV rates among FDRs across the literature. A gradual decrease of the incremental effect was found with the increase in screening age.

Conclusion

This economic evaluation model found that echocardiographic screening of FDRs of a BAV index case is not only clinically important but also cost-effective and cost-saving. Sensitivity analysis supported the model's robustness, suggesting its generalization.
Delayed Tree Mortality After Prescribed Fires in Mixed Oak Forests in Northwestern Ohio
Authors: Abella Scott R , Sprow LaRae A , Schetter Timothy A
Published: July 2021

Delayed tree mortality can contribute to variability in fire effects in forests, but its prevalence is not well understood in eastern North American oak forests where a management goal is using prescribed fire to shape forest density and composition. To assess potential delayed mortality after prescribed fires, we tracked the fates of 690 trees of four species in burned and 542 trees in unburned oak forests in northwestern Ohio, USA, and modeled survival using tree diameter and bole char. Delayed mortality, occurring 3–4 growing seasons after fire and in addition to initial mortality (1–2 growing seasons after fire), varied with species and tree diameter. Compared to initial mortality, delayed mortality resulted in eleven times more small-diameter (1–13 cm) red maple (Acer rubrum) dying after fire. White oak (Quercus alba), 1–25 cm in diameter, also incurred delayed mortality (five-times increase in dead trees). Neither sassafras (Sassafras albidum) nor black oak (Quercus velutina) displayed delayed mortality. Background tree mortality in unburned sites was minimal (0.4% per year across species). Logistic regression to model canopy survival selected only stem diameter for burned red maple trees, whereas both diameter and bole char related to survival in other species. Results suggest that (1) monitoring postfire tree mortality in oak forests should extend for at least four growing seasons to detect delayed mortality in some species, and that (2) single surface fires may eventually reduce encroaching red maple in oak forests more than initial postfire years indicate.
Constraint of glacial isostatic adjustment in the North Sea with geological relative sea level and GNSS vertical land motion data
Authors: Simon K M , Riva R E M , Vermeersen L L A
Published: July 2021

In this study, we focus on improved constraint of the glacial isostatic adjustment (GIA) signal at present-day, and its role as a contributor to present-day sea level budgets. The main study area extends from the coastal regions of northwestern Europe to northern Europe. Both Holocene relative sea level (RSL) data as well as vertical land motion (VLM) data are incorporated as constraints in a semi-empirical GIA model. 71 geological rates of GIA-driven RSL change are inferred from Holocene proxy data and 108 rates of vertical land motion from GNSS provide an additional measure of regional GIA deformation. Within the study area, the geological RSL data complement the spatial gaps of the VLM data and vice versa. Both data sets are inverted in a semi-empirical GIA model to yield updated estimates of regional present-day GIA deformations. A regional validation using tide gauges is presented for the North Sea, where the GIA signal may be complicated by lateral variations in Earth structure and existing predictions of regional and global GIA models show discrepancies. The model validation in the North Sea region suggests that geological data are needed to fit independent estimates of GIA-related RSL change inferred from tide gauge rates, indicating that geological rates from Holocene data do provide an important additional constraint for data-driven approaches to GIA estimation.
Machine Learning Models Under the Copyright Microscope: Is EU Copyright Fit for Purpose?
Authors: Otero BegoÑa Gonzalez
Published: July 2021

This paper is based on a presentation given in December 2019 at the Lund’s University conference ‘Artificial Intelligence (AI), Data Protection and Intellectual Property in a European context’. The purpose of this article is to analyse the suitability of the copyright system over Machine Learning (ML) models, the so-called ‘core components’ of ML systems. Computer programs protection has always caused certain difficulties for intellectual property law. Internationally, agreement was reached in the 1970s to protect computer programs as literary works of copyright. ML models have been called ‘learning algorithms’, ‘AI computer programs’, and ‘software 2.0’. Yet there is no unanimity about what they are technically. This is relevant from a copyright perspective, because the regime of protection granted by copyright will be different depending on whether the ML model qualifies as a computer program, as a mathematical method, or as another type of work. Additionally, all proprietary and open source software licensing relies on copyright protection. In most open licenses, the license is not triggered if it is applied to something that is not protected by copyright (or related rights). Thus, it seems pertinent to question whether EU copyright law provides adequate protection for the core components of machine learning systems, the ML models.
CFAP65 is required in the acrosome biogenesis and mitochondrial sheath assembly during spermiogenesis
Authors: Wang Weili , Tian Shixong , Nie Hongchuan , Tu Chaofeng , Liu Chunyu , Li Yong , Li Dongyan , Yang Xiaoxuan , Meng Lanlan , Hu Tongyao , Zhang Qianjun , Du Juan , Fan Liqing , Lu Guangxiu , Lin Ge , Zhang Feng , Tan Yue-Qiu
Published: July 2021

Asthenoteratospermia is a common cause of male infertility. Recent studies have revealed that CFAP65 mutations lead to severe asthenoteratospermia due to acrosome hypoplasia and flagellum malformations. However, the molecular mechanism underlying CFAP65-associated sperm malformation is largely unclear. Here, we initially examined the role of CFAP65 during spermiogenesis using Cfap65 knockout (Cfap65−/−) mice. The results showed that Cfap65−/− male mice exhibited severe asthenoteratospermia characterized by morphologically defective sperm heads and flagella. In Cfap65−/− mouse testes, hyper-constricted sperm heads were apparent in step 9 spermatids accompanied by abnormal manchette development, and acrosome biogenesis was abnormal in the maturation phase. Moreover, subsequent flagellar elongation was also severely affected and characterized by disrupted assembly of the mitochondrial sheath (MS) in Cfap65−/− male mice. Furthermore, the proteomic analysis revealed that the proteostatic system during acrosome formation, manchette organization and MS assembly was disrupted when CFAP65 was lost. Importantly, endogenous immunoprecipitation and immunostaining experiments revealed that CFAP65 may form a cytoplasmic protein network comprising MNS1, RSPH1, TPPP2, ZPBP1 and SPACA1. Overall, these findings provide insights into the complex molecular mechanisms of spermiogenesis by uncovering the essential roles of CFAP65 during sperm head shaping, acrosome biogenesis and MS assembly.
Dynamic control of nucleic-acid-sensing Toll-like receptors by the endosomal compartment
Authors: Miyake Kensuke , Saitoh Shin-Ichiroh , Fukui Ryutaro , Shibata Takuma , Sato Ryota , Murakami Yusuke
Published: July 2021

Nucleic-acid (NA)-sensing Toll-like receptors (TLRs) are synthesized in the endoplasmic reticulum and mature with chaperones, such as Unc93B1 and the protein associated with TLR4 A (PRAT4A)–gp96 complex. The TLR–Unc93B1 complexes move to the endosomal compartment, where proteases such as cathepsins activate their responsiveness through proteolytic cleavage of the extracellular domain of TLRs. Without proteolytic cleavage, ligand-dependent dimerization of NA-sensing TLRs is prevented by the uncleaved loop in the extracellular domains. Additionally, the association of Unc93B1 inhibits ligand-dependent dimerization of TLR3 and TLR9 and, therefore, Unc93B1 is released from these TLRs before dimerization. Ligand-activated NA-sensing TLRs induce the production of pro-inflammatory cytokines and act on the endosomal compartment to initiate anterograde trafficking to the cell periphery for type I interferon production. In the endosomal compartment, DNA and RNA are degraded by DNases and RNases, respectively, generating degradation products. DNase 2A and RNase T2 generate ligands for TLR9 and TLR8, respectively. In this mechanism, DNases and RNases control innate immune responses to NAs in endosomal compartments. NA-sensing TLRs and the endosomal compartment work together to monitor environmental cues through endosomes and decide to launch innate immune responses.
Disentangling data dependency using cross-validation strategies to evaluate prediction quality of cattle grazing activities using machine learning algorithms and wearable sensor data
Authors: Coelho Ribeiro Leonardo Augusto , Bresolin Tiago , Rosa Guilherme Jordão de Magalhães , Rume Casagrande Daniel , Danes Marina de Arruda Camargo , Dórea João Ricardo Rebouças
Published: July 2021

Wearable sensors have been explored as an alternative for real-time monitoring of cattle feeding behavior in grazing systems. To evaluate the performance of predictive models such as machine learning (ML) techniques, data cross-validation (CV) approaches are often employed. However, due to data dependencies and confounding effects, poorly performed validation strategies may significantly inflate the prediction quality. In this context, our objective was to evaluate the effect of different CV strategies on the prediction of grazing activities in cattle using wearable sensor (accelerometer) data and ML algorithms. Six Nellore bulls (average live weight of 345 ± 21 kg) had their behavior visually classified as grazing or not-grazing for a period of 15 d. Elastic Net Generalized Linear Model (GLM), Random Forest (RF), and Artificial Neural Network (ANN) were employed to predict grazing activity (grazing or not-grazing) using 3-axis accelerometer data. For each analytical method, three CV strategies were evaluated: holdout, leave-one-animal-out (LOAO), and leave-one-day-out (LODO). Algorithms were trained using similar dataset sizes (holdout: n = 57,862; LOAO: n = 56,786; LODO: n = 56,672). Overall, GLM delivered the worst prediction accuracy (53%) compared with the ML techniques (65% for both RF and ANN), and ANN performed slightly better than RF for LOAO (73%) and LODO (64%) across CV strategies. The holdout yielded the highest nominal accuracy values for all three ML approaches (GLM: 59%, RF: 76%, and ANN: 74%), followed by LODO (GLM: 49%, RF: 61%, and ANN: 63%) and LOAO (GLM: 52%, RF: 57%, and ANN: 57%). With a larger dataset (i.e., more animals and grazing management scenarios), it is expected that accuracy could be increased. Most importantly, the greater prediction accuracy observed for holdout CV may simply indicate a lack of data independence and the presence of carry-over effects from animals and grazing management. Our results suggest that generalizing predictive models to unknown (not used for training) animals or grazing management may incur poor prediction quality. The results highlight the need for using management knowledge to define the validation strategy that is closer to the real-life situation, i.e., the intended application of the predictive model.
Relationship Between Scorpion Stings Events and Environmental Conditions in Mainland France
Authors: Vaucel Jules-Antoine , Larréché Sébastien , Paradis Camille , Labadie Magali , Courtois Arnaud , Grenet Guillaume , Langrand Jérome , Tournoud Christine , Nisse Patrick , Gallart Jean-Christophe , Schmitt Corinne , Torrents Romain , Le Roux Gaël , Gil-Jardine Cédric , Kallel Hatem ,   French PCC Research Group, Deguigne Marie , Descatha Alexis , Patat Anne-Marie , Paret Nathalie , Blanc-Brisset Ingrid , Nardon Audrey , de Haro Luc , Simon Nicolas , Delcourt Nicolas , Pelissier Fanny , Puskarczyk Emmanuel , Laborde-Casterot Hervé , Care Weniko , Vodovar Dominique
Published: July 2021

In the world, the impact of environmental conditions on the number of scorpion events was evaluated in North Africa,Middle East, and the Amazonian region but not in Europe. In mainland France, scorpion species described are Buthus occitanus (Amoreux, 1789), Belisarius xambeui (Simon, 1879) and 4 Euscorpiidae: Euscorpius concinnus (Koch, 1837), Euscorpius italicus (Herbst, 1800), Euscorpius tergestinus (Koch, 1837), and Tetratrichobothrius flavicaudis (De Geer, 1778). We aimed to describe the impact of environmental conduction on the number of scorpion events. For this, a retrospective multi-center study was conducted with data from the French poison control centers files about scorpion events between 1 January 2011 and 31 December 2020. During the study period, 975 incoming calls for scorpion events were recorded and 574 were related to scorpions native to mainland France and Corsica: B. occitanus (n = 86), Euscorpiidae species (n = 222), B. xambeui (n = 1), and undetermined species (n = 265). Cases were mostly reported along the Mediterranean coast, along rivers, and in cities with a trading port. The number of scorpion events was linked to the rivers' water level, rivers' flow, temperature, sunshine, and pluviometry (P < 0.05 for all variables). B. occitanus need warmest and driest environment than Euscorpiidae spp. A link between the severity of the envenoming and climatic condition or seasonality was not demonstrated.
The Tianlai dish pathfinder array: design, operation, and performance of a prototype transit radio interferometer
Authors: Wu Fengquan , Li Jixia , Zuo Shifan , Chen Xuelei , Das Santanu , Marriner John P , Oxholm Trevor M , Phan Anh , Stebbins Albert , Timbie Peter T , Ansari Reza , Campagne Jean-Eric , Chen Zhiping , Cong Yanping , Huang Qizhi , Kwak Juhun , Li Yichao , Liu Tao , Liu Yingfeng , Niu Chenhui , Osinga Calvin , Perdereau Olivier , Peterson Jeffrey B , Podczerwinski John , Shi Huli , Siebert Gage , Sun Shijie , Tian Haijun , Tucker Gregory S , Wang Qunxiong , Wang Rongli , Wang Yougang , Wu Yanlin , Xu Yidong , Yu Kaifeng , Yu Zijie , Zhang Jiao , Zhang Juyong , Zhu Jialu
Published: July 2021

The Tianlai Dish Pathfinder Array is a radio interferometer designed to test techniques for 21 cm intensity mapping in the post-reionization universe as a means for measuring large-scale cosmic structure. It performs drift scans of the sky at constant declination. We describe the design, calibration, noise level, and stability of this instrument based on the analysis of about 5% of 6200 h of on-sky observations through 2019 October. Beam pattern determinations using drones and the transit of bright sources are in good agreement, and compatible with electromagnetic simulations. Combining all the baselines, we make maps around bright sources and show that the array behaves as expected. A few hundred hours of observations at different declinations have been used to study the array geometry and pointing imperfections, as well as the instrument noise behaviour. We show that the system temperature is below 80 K for most feed antennas and that noise fluctuations decrease as expected with integration time, at least up to a few hundred seconds. Analysis of long integrations, from 10 nights of observations of the North Celestial Pole (NCP), yielded visibilities with amplitudes of 20–30 mK, consistent with the expected signal from the NCP radio sky with ${\lt}10\,$ mK precision for 1 MHz × 1 min binning. Hi-pass filtering the spectra to remove smooth spectrum signal yields a residual consistent with zero signal at the $0.5\,$ mK level.
Statistical recovery of the BAO scale from multipoles of the beam-convolved 21 cm correlation function
Authors: Kennedy Fraser , Bull Philip
Published: July 2021

Despite being designed as an interferometer, the MeerKAT radio array (a Square Kilometre Array pathfinder) can also be used in autocorrelation (‘single-dish’) mode, where each dish scans the sky independently. Operating in this mode allows extremely high survey speeds to be achieved, albeit at significantly lower angular resolution. We investigate the recovery of the baryon acoustic oscillation (BAO) scale from multipoles of the redshift-space correlation function as measured by a low angular resolution 21 cm intensity mapping survey of this kind. Our approach is to construct an analytic model of the multipoles of the correlation function and their covariance matrix that includes foreground contamination and beam resolution effects, which we then use to generate an ensemble of mock data vectors from which we attempt to recover the BAO scale. In line with previous studies, we find that recovery of the transverse BAO scale α⊥ is hampered by the strong smoothing effect of the instrumental beam with increasing redshift, while the radial scale α∥ is much more robust. The multipole formalism naturally incorporates transverse information when it is available however, and so there is no need to perform a radial-only analysis. In particular, the quadrupole of the correlation function preserves a distinctive BAO ‘bump’ feature even for large smoothing scales. We also investigate the robustness of BAO scale recovery to beam model accuracy, severity of the foreground removal cuts, and accuracy of the covariance matrix model, finding in all cases that the radial BAO scale can be recovered in an accurate, unbiased manner.
Carbon-enhanced stars with short orbital and spin periods
Authors: Whitehouse L J , Farihi J , Howarth I D , Mancino S , Walters N , Swan A , Wilson T G , Guo J
Published: July 2021

Many characteristics of dwarf carbon stars are broadly consistent with a binary origin, including mass transfer from an evolved companion. While the population overall appears to have old-disc or halo kinematics, roughly 2 per cent of these stars exhibit  Hα emission, which in low-mass main-sequence stars is generally associated with rotation and relative youth. Its presence in an older population therefore suggests either irradiation or spin-up. This study presents time-series analyses of photometric and radial-velocity data for seven dwarf carbon stars with  Hα emission. All are shown to have photometric periods in the range 0.2–5.2 d, and orbital periods of similar length, consistent with tidal synchronization. It is hypothesized that dwarf carbon stars with emission lines are the result of close-binary evolution, indicating that low-mass, metal-weak, or metal-poor stars can accrete substantial material prior to entering a common-envelope phase.
Spiral instabilities: little interaction with a live halo
Authors: Sellwood J A
Published: July 2021

In order to address the question of whether spiral disturbances in galaxy discs are gravitationally coupled to the halo, we conduct simulations of idealized models of disc galaxies. We compare growth rates of spiral instabilities in identical mass models in which the halo is held rigid or is represented by particles drawn from an equilibrium distribution function. We examine cases of radial and azimuthal bias in the halo velocity ellipsoid in one of our models, and an isotropic velocity distribution in both. We find at most marginal evidence for an enhanced growth rate of spiral modes caused by a halo supporting response. We also find evidence for very mild dynamical friction between the spiral disturbance and the halo. We offer an explanation to account for the different behaviour between spiral modes and bar modes, since earlier work had found that bar instabilities became significantly more vigorous when a responsive halo was substituted for an equivalent rigid mass distribution. The barely significant differences found here justify the usual simplifying approximation of a rigid halo made in studies of spiral instabilities in galaxies.
RENET2: high-performance full-text gene–disease relation extraction with iterative training data expansion
Authors: Su Junhao , Wu Ye , Ting Hing-Fung , Lam Tak-Wah , Luo Ruibang
Published: July 2021

Relation extraction (RE) is a fundamental task for extracting gene–disease associations from biomedical text. Many state-of-the-art tools have limited capacity, as they can extract gene–disease associations only from single sentences or abstract texts. A few studies have explored extracting gene–disease associations from full-text articles, but there exists a large room for improvements. In this work, we propose RENET2, a deep learning-based RE method, which implements Section Filtering and ambiguous relations modeling to extract gene–disease associations from full-text articles. We designed a novel iterative training data expansion strategy to build an annotated full-text dataset to resolve the scarcity of labels on full-text articles. In our experiments, RENET2 achieved an F1-score of 72.13% for extracting gene–disease associations from an annotated full-text dataset, which was 27.22, 30.30, 29.24 and 23.87% higher than BeFree, DTMiner, BioBERT and RENET, respectively. We applied RENET2 to (i) ∼1.89M full-text articles from PubMed Central and found ∼3.72M gene–disease associations; and (ii) the LitCovid articles and ranked the top 15 proteins associated with COVID-19, supported by recent articles. RENET2 is an efficient and accurate method for full-text gene–disease association extraction. The source-code, manually curated abstract/full-text training data, and results of RENET2 are available at GitHub.
ECOA-5. Integrative 3D spatial characterization of genomic and epigenomic intratumoral heterogeneity in glioblastoma
Authors: Mathur Radhika , Wang Qixuan , Schupp Patrick , Hilz Stephanie , Hong Chibo , Smirnov Ivan , Lafontaine Marisa , Nair Devika , Iyyanaki Sriranga , Phillips Joanna , Chang Susan , Li Yan , Lupo Janine , Oldham Michael , Yue Feng , Costello Joseph
Published: July 2021

Treatment failure in glioblastoma is often attributed to intratumoral heterogeneity (ITH), which fosters tumor evolution and selection of therapy-resistant clones. While genomic alterations are known contributors to ITH, emerging studies highlight functional roles for epigenomic ITH which integrates differentiation status, stochastic events, and microenvironmental inputs. Here, we have established a novel platform for integrative characterization of genomic and epigenomic ITH of glioblastoma in three-dimensional (3-D) space. In collaboration with neurosurgeons and biomedical imaging experts, we utilize 3-D surgical neuro-navigation to safely acquire ~10 tumor samples per patient representing maximal anatomical diversity. We conduct whole-exome sequencing, RNA sequencing, and assay for transposase-accessible chromatin using sequencing (ATAC-Seq) on each sample. The spatial location of each sample is mapped by its 3-D coordinates, allowing 360-degree visualization of genomic and epigenomic ITH for each patient. We demonstrate this approach on 8 patients with primary IDH-WT glioblastoma (83 spatially mapped samples), providing unprecedented insight into their spatial organization at the genomic and epigenomic levels. We link genetically defined tumor subclones to patterns of open chromatin and gene regulation, revealing underlying transcription factor binding at active promoters and enhancers. We also identify ITH in whole-genome doubling and focal oncogene amplification events in multiple patients, which we then link with epigenomic ITH. Further, to study microenvironmental inputs and their contribution to epigenomic ITH, we conduct deconvolution of RNA sequencing and ATAC-Seq data by analyzing feature co-variation. We resolve the 3-D spatial organization of immune, neural, and other nontumor cell types present in glioblastoma, characterizing their functional states and interactions with tumor cells. This work provides the most comprehensive spatial characterization of genomic and epigenomic ITH to date in glioblastoma. As a resource for further investigation, we have developed an interactive data sharing platform – The 3D Glioma Atlas – that enables 360-degree visualization of both genomic and epigenomic ITH.
ECOA-10. Integrated genomic and clinical analysis of BRAF-mutated glioma in adults
Authors: Langat Pinky , Li Taibo , Bi Wenya Linda , Schreck Karisa C
Published: July 2021

BRAF alterations are recognized as a significant driver of disease in pediatric low-grade glioma (pLGG) but the implications of BRAF alterations on the natural history and response to treatment are unclear in adult glioma. We characterized the molecular and clinical features of a multi-institutional cohort of adults with BRAF-mutated gliomas. We identified patients with glioma containing BRAF alterations on sequencing in multi-institutional cohorts (Dana-Farber/Brigham Cancer Center, Johns Hopkins Hospital, GENIE, TCGA). BRAF alterations were grouped into previously defined classes: I (V600E; RAS-independent/dimerization-independent), II (RAS-independent/dimerization-dependent), III (RAS-dependent/dimerization-dependent) in addition to BRAF copy number gains, fusions, and other. We interrogated 289 BRAF-altered gliomas (199 patients >=18yrs, 90 patients <18yrs; range 0-85yrs), and observed histopathologic and molecular differences between BRAF-altered gliomas in adults versus pediatric patients. Amongst adults, the most common BRAF alterations were Class I followed by copy number gains, with glioblastoma (GBM) the most prevalent histology. In comparison, pediatric gliomas in our cohort frequently harbored Class I mutations followed by BRAF fusions, with primarily pilocytic astrocytoma and pLGG histologies. Principal component analysis and correlation analysis revealed molecular features associated with gliomas of different BRAF alterations and histologies, including mutation of NF1, a negative regulator of RAS, which was significantly associated with class II/III BRAF alterations (64.3%) and not observed in BRAFV600E-mutated gliomas (0%, n=62) (p<0.0001). Demographic and molecular features were evaluated for correlates for adult glioma risk stratification. Comparative survival analysis showed no significant difference between adult GBM harboring Class I compared to other BRAF alterations, whereas young adult age (18-35yrs) was associated with improved outcomes (p<0.05). Among 86 GBM patients with detailed clinicopathologic data, 7 received RAF-targeted therapy, with variable clinical response. This cohort of BRAF-altered adult gliomas demonstrates a broad range of molecular alterations with implications for treatment sensitivity and patient risk stratification.
MOMC-5. Systems pharmacogenomics identifies novel targets and clinically actionable therapeutics for medulloblastoma
Authors: Genovesi Laura , Millar Amanda , Tolson Elissa , Singleton Matthew , Hassall Emily , Kojic Marija , Brighi Caterina , Girald Emily , Andradas Clara , Kuchibhotla Mani , Endersby Raelene , Gottardo Nicholas , Bernard Anne , Adolphe Christelle , Olson James , Davis Melissa , Wainwright Brandon
Published: July 2021

Background

Medulloblastoma (MB) is the most common malignant paediatric brain tumour and a leading cause of cancer-related mortality and morbidity. Existing treatment protocols are aggressive in nature resulting in significant neurological, intellectual and physical disabilities for the children undergoing treatment. Clearly, there is an urgent need for improved, targeted therapies that minimize these harmful side effects.

Methods

We identified candidate drugs for MB using a network-based systems-pharmacogenomics approach: based on results from a functional genomics screen, we identified a network of interactions implicated in human MB growth regulation. We then integrated drugs and their known mechanisms of action, along with gene expression data from a large collection of medulloblastoma patients to identify drugs with potential to treat MB.

Results

Our analyses identified drugs targeting CDK4, CDK6, and AURKA as strong candidates for MB; all of these genes are well validated as drug targets in other tumour types. We also identified non-WNT MB as a novel indication for drugs targeting TUBB, CAD, SNRPA, SLC1A5, PTPRS, P4HB and CHEK2. Based upon these analyses we subsequently demonstrated that one of these drugs, the new microtubule stabilizing agent, ixabepilone, blocked tumour growth in vivo in mice bearing Sonic Hedgehog and Group 3 patient-derived xenograft tumours, providing the first demonstration of its efficacy in MB.

Conclusions

Our findings confirm that this data-driven systems pharmacogenomics strategy is a powerful approach for the discovery and validation of novel therapeutic candidates relevant to MB treatment, and along with data validating ixabepilone in PDX models of the two most aggressive subtypes of medulloblastoma, we present the network analysis framework as a resource for the field.
NGMA-4. Creation of a MADR brain tumor single-cell atlas for examination of inter-/intratumor heterogeneity and the results of genetic perturbations in a diverse array of brain tumor subtypes
Authors: Pacheco David Rincon Fernandez , Park Hannah , Grausam Katie , Breunig Joshua
Published: July 2021

We have recently established mosaic analysis by dual recombinase-mediated cassette exchange (MADR), which permits stable labeling of mutant cells expressing transgenic elements from precisely defined chromosomal loci. MADR provides a toolkit of elements for combinatorial labeling, inducible/reversible transgene manipulation, VCre recombinase expression, and genetic manipulation of human cells. Further, we have demonstrated the versatility of MADR by creating glioma models with mixed, reporter-identified zygosity or with “personalized” driver mutations from pediatric glioma. For example, introducing H3f3a (aka H3.3) mutation variants with MADR regulates the spatiotemporal profile of glioma, and single-cell RNA and ATAC sequencing analysis demonstrates a recapitulation of developmental hierarchy seen in K27M mutant human glioma. Moreover, we have generated novel models of H3.3 WT glioma, H3.3 G34R glioma, and supratentorial ependymoma using patient-derived oncofusion transgenes. These models display a high degree of phenotypic fidelity and we now compare these models on a single-cell level with our previous models, mouse single-cell RNA glioma datasets from other studies, and human tumor cell transcriptomes. Our multi-omics approach includes integration of ChIP-seq/Cut&Tag datasets, single-cell ATAC, and single-cell Cut&Tag datasets.

Moreover, we have engineered a novel methodology for inducible gain- and loss-of function perturbation studies in vivo. Using ETS transcription factors as a proof-of-principle, we overlay these genetic perturbations on the glioma atlas to examine the gene networks altered by precise molecular manipulations.

We hope that these combined approaches will enable researchers to discover disease mechanisms with increased resolution and test therapeutics in credentialed pre-clinical disease models.
OPTC-3. Differential Synapse-Related Gene Expression Identifies Glioma Subtypes and Predicts Prognosis
Authors: Surapaneni Akhil , Kohli Vik , Ahmed Yousuf , Seghers Matthew , Kuo John
Published: July 2021

Synaptic connectivity between gliomas and adjacent brain was recently implicated in tumorigenesis. However, the interaction of synapse-related genes (SRGs) with patient survival and with established clinical and molecular glioma subtypes merit further study in a large patient cohort. We characterized differential expression of SRGs in gliomas and investigated SRG expression as putative clinical biomarkers in a large glioma cohort.

Expression of 1189 SRGs was interrogated via RNA sequencing analysis in 603 gliomas (LGG n=451, GBM n=152) of The Cancer Genome Atlas. SRG expression patterns partitioned gliomas into two clusters that were more distinctive than priorly identified glioma subtypes. The two glioma clusters showed significantly low (14.9 months) or high median survival (105.1 months; Hazard Ratio = 7.1, 95% CI: [5.32, 9.78], p = 1.29e-46 using a log-rank test). The high survival cluster showed overrepresentation of known pro-neural and neural subtypes and IDH-mutated gliomas (p<0.00001). The mesenchymal and classic GBMs and IDH-wild type gliomas were overrepresented in the low survival cluster (p < 0.00001). In addition, an Elastic Net Cox Regression model identified 34 SRGs whose expression significantly predicted differential survival and a prognostic Synapse Gene Score (SGS) was created. Using an accelerated failure time model, SGS predicted survival in the overall gliomas after adjusting for IDH-1 mutation (HR = 2.51, 95% CI: [2.27, 2.7496], p<0.00001), and in the IDH-1 mutant cohort after adjusting for 1p/19q co-deletion (HR = 2.05, 95% CI: [1.73, 2.37], p<0.00001).

Our analysis shows that gliomas can be distinctively clustered by differential SRGs expression, suggesting that synapse-related proteins may contribute to tumorigenesis via multiple mechanisms. Furthermore, the potential utility of SRGs as clinical glioma biomarkers is supported by our creation of a prognostic SGS. Future studies elucidating interactions between tumorigenesis and synaptic mechanisms may reveal additional insights for glioma biology and therapeutic targeting.