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1. sbi reloaded: a toolkit for simulation-based inference workflows

Author

Boelts, Jan, Deistler, Michael, Gloeckler, Manuel, Tejero-Cantero, Álvaro, Lueckmann, Jan-Matthis, Moss, Guy, Steinbach, Peter, Moreau, Thomas, Muratore, Fabio, Linhart, Julia, Durkan, Conor, Vetter, Julius, Miller, Benjamin Kurt, Herold, Maternus, Ziaeemehr, Abolfazl, Pals, Matthijs, Gruner, Theo, Bischoff, Sebastian, Krouglova, Nastya, Gao, Richard, Lappalainen, Janne K., Mucsányi, Bálint, Pei, Felix, Schulz, Auguste, Stefanidi, Zinovia, Rodrigues, Pedro, Schröder, Cornelius, Zaid, Faried Abu, Beck, Jonas, Kapoor, Jaivardhan, Greenberg, David S., Gonçalves, Pedro J., and Macke, Jakob H.

Subjects
Computer Science - Machine Learning
Abstract

Scientists and engineers use simulators to model empirically observed phenomena. However, tuning the parameters of a simulator to ensure its outputs match observed data presents a significant challenge. Simulation-based inference (SBI) addresses this by enabling Bayesian inference for simulators, identifying parameters that match observed data and align with prior knowledge. Unlike traditional Bayesian inference, SBI only needs access to simulations from the model and does not require evaluations of the likelihood-function. In addition, SBI algorithms do not require gradients through the simulator, allow for massive parallelization of simulations, and can perform inference for different observations without further simulations or training, thereby amortizing inference. Over the past years, we have developed, maintained, and extended $\texttt{sbi}$, a PyTorch-based package that implements Bayesian SBI algorithms based on neural networks. The $\texttt{sbi}$ toolkit implements a wide range of inference methods, neural network architectures, sampling methods, and diagnostic tools. In addition, it provides well-tested default settings but also offers flexibility to fully customize every step of the simulation-based inference workflow. Taken together, the $\texttt{sbi}$ toolkit enables scientists and engineers to apply state-of-the-art SBI methods to black-box simulators, opening up new possibilities for aligning simulations with empirically observed data.

Published
2024

2. When Knockoffs fail: diagnosing and fixing non-exchangeability of Knockoffs

Author

Blain, Alexandre, Thirion, Bertrand, Linhart, Julia, and Neuvial, Pierre

Subjects
Statistics - Methodology
Abstract

Knockoffs are a popular statistical framework that addresses the challenging problem of conditional variable selection in high-dimensional settings with statistical control. Such statistical control is essential for the reliability of inference. However, knockoff guarantees rely on an exchangeability assumption that is difficult to test in practice, and there is little discussion in the literature on how to deal with unfulfilled hypotheses. This assumption is related to the ability to generate data similar to the observed data. To maintain reliable inference, we introduce a diagnostic tool based on Classifier Two-Sample Tests. Using simulations and real data, we show that violations of this assumption occur in common settings for classical Knockoffs generators, especially when the data have a strong dependence structure. We show that the diagnostic tool correctly detects such behavior. To fix knockoff generation, we propose a nonparametric, computationally-efficient alternative knockoff construction, which is based on constructing a predictor of each variable based on all others. We show that this approach achieves asymptotic exchangeability with the original variables under standard assumptions on the predictive model. We show empirically that the proposed approach restores error control on simulated data.

Published
2024

5. Diffusion posterior sampling for simulation-based inference in tall data settings

Author

Linhart, Julia, Cardoso, Gabriel Victorino, Gramfort, Alexandre, Corff, Sylvain Le, and Rodrigues, Pedro L. C.

Subjects
Statistics - Machine Learning, Computer Science - Machine Learning, Statistics - Methodology
Abstract

Determining which parameters of a non-linear model best describe a set of experimental data is a fundamental problem in science and it has gained much traction lately with the rise of complex large-scale simulators. The likelihood of such models is typically intractable, which is why classical MCMC methods can not be used. Simulation-based inference (SBI) stands out in this context by only requiring a dataset of simulations to train deep generative models capable of approximating the posterior distribution that relates input parameters to a given observation. In this work, we consider a tall data extension in which multiple observations are available to better infer the parameters of the model. The proposed method is built upon recent developments from the flourishing score-based diffusion literature and allows to estimate the tall data posterior distribution, while simply using information from a score network trained for a single context observation. We compare our method to recently proposed competing approaches on various numerical experiments and demonstrate its superiority in terms of numerical stability and computational cost., Comment: 49 pages, 24 figures, 3 tables, 2 algorithms, 12 appendices, in proceedings

Published
2024

10. Head-to-head trial of pegunigalsidase alfa versus agalsidase beta in patients with Fabry disease and deteriorating renal function: results from the 2-year randomised phase III BALANCE study.

Author

Wallace, Eric, Goker-Alpan, Ozlem, Wilcox, William, Holida, Myrl, Bernat, John, Longo, Nicola, Linhart, Aleš, Hughes, Derralynn, Hopkin, Robert, Tøndel, Camilla, Langeveld, Mirjam, Giraldo, Pilar, Pisani, Antonio, Germain, Dominique, Mehta, Ankit, Deegan, Patrick, Molnar, Maria, Ortiz, Damara, Jovanovic, Ana, Muriello, Michael, Barshop, Bruce, Kimonis, Virginia, Vujkovac, Bojan, Nowak, Albina, Geberhiwot, Tarekegn, Kantola, Ilkka, Knoll, Jasmine, Waldek, Stephen, Nedd, Khan, Karaa, Amel, Brill-Almon, Einat, Alon, Sari, Chertkoff, Raul, Rocco, Rossana, Sakov, Anat, and Warnock, David

Subjects
Drug-Related Side Effects and Adverse Reactions, Fabry Disease, Genetic Diseases, Inborn, Genetic Diseases, X-Linked, alpha-Galactosidase, Humans, Fabry Disease, Male, alpha-Galactosidase, Adult, Female, Middle Aged, Glomerular Filtration Rate, Enzyme Replacement Therapy, Isoenzymes, Recombinant Proteins, Adolescent, Young Adult, Treatment Outcome
Abstract

BACKGROUND: Pegunigalsidase alfa is a PEGylated α-galactosidase A enzyme replacement therapy. BALANCE (NCT02795676) assessed non-inferiority of pegunigalsidase alfa versus agalsidase beta in adults with Fabry disease with an annualised estimated glomerular filtration rate (eGFR) slope more negative than -2 mL/min/1.73 m2/year who had received agalsidase beta for ≥1 year. METHODS: Patients were randomly assigned 2:1 to receive 1 mg/kg pegunigalsidase alfa or agalsidase beta every 2 weeks for 2 years. The primary efficacy analysis assessed non-inferiority based on median annualised eGFR slope differences between treatment arms. RESULTS: Seventy-seven patients received either pegunigalsidase alfa (n=52) or agalsidase beta (n=25). At baseline, mean (range) age was 44 (18-60) years, 47 (61%) patients were male, median eGFR was 74.5 mL/min/1.73 m2 and median (range) eGFR slope was -7.3 (-30.5, 6.3) mL/min/1.73 m2/year. At 2 years, the difference between median eGFR slopes was -0.36 mL/min/1.73 m2/year, meeting the prespecified non-inferiority margin. Minimal changes were observed in lyso-Gb3 concentrations in both treatment arms at 2 years. Proportions of patients experiencing treatment-related adverse events and mild or moderate infusion-related reactions were similar in both groups, yet exposure-adjusted rates were 3.6-fold and 7.8-fold higher, respectively, with agalsidase beta than pegunigalsidase alfa. At the end of the study, neutralising antibodies were detected in 7 out of 47 (15%) pegunigalsidase alfa-treated patients and 6 out of 23 (26%) agalsidase beta-treated patients. There were no deaths. CONCLUSIONS: Based on rate of eGFR decline over 2 years, pegunigalsidase alfa was non-inferior to agalsidase beta. Pegunigalsidase alfa had lower rates of treatment-emergent adverse events and mild or moderate infusion-related reactions. TRIAL REGISTRATION NUMBER: NCT02795676.

Published
2024

11. Clinical management of female patients with Fabry disease based on expert consensus

Author

Eva Brand, Aleš Linhart, Patrick Deegan, Ruxandra Jurcut, Antonio Pisani, Roser Torra, and Ulla Feldt-Rasmussen

Subjects
Fabry disease, Female, Early diagnosis, Enzyme replacement therapy, Patient-reported outcome measures, Medicine
Abstract

Abstract Fabry disease is an X-linked lysosomal storage disorder that causes accumulation of glycosphingolipids in body tissues and fluids, leading to progressive organ damage and life-threatening complications. It can affect both males and females and can be classified into classic or later-onset phenotypes. The disease severity in females ranges from asymptomatic to the more severe, classic phenotype. Most females are hemizygous and the X-linked inheritance is associated with variable X-activation pattern and residual enzymatic activity. The heterogeneity of clinical presentation in females requires different approaches to diagnosis and management than males. A European group of 7 physicians, experienced in the management of Fabry disease, convened to discuss patient perspectives and published guidelines. The experts discussed the need to focus on psychological treatment in relation to individual coping styles when monitoring targets, and the lack of data supporting the use of plasma globotriaosylsphingosine over enzyme activity in the diagnosis of these patients. It was suggested that the high phenotypic variability in female patients may be related to the dynamic nature of the X-chromosome inactivation process and further understanding of this process could help predict the progression of Fabry disease in females and facilitate timely intervention. Due to the range of disease severity they exhibit, female patients with Fabry disease may require a more individualized treatment approach than males. Despite current recommendations, the experts agreed that early disease-specific treatment initiation in high-risk females could improve clinical outcome.

Published
2025
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12. Fertilization by short-term stored sperm alters DNA methylation patterns at single-base resolution in common carp (Cyprinus carpio) embryos

Author

Cheng, Yu, Zhang, Songpei, Nayak, Rigolin, Věchtová, Pavlína, Schumacher, Fabian, Linhartová, Pavla, Gazo, Ievgeniia, Linhartová, Zuzana, Waghmare, Swapnil Gorakh, Kleuser, Burkhard, Dey, Abhipsha, Rodinová, Vladimíra, Rodina, Marek, Štěrba, Jan, Alavi, Sayyed Mohammad Hadi, Labbé, Catherine, and Linhart, Otomar

Published
2024
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14. Prevention of cerebral thromboembolism by oral anticoagulation with dabigatran after pulmonary vein isolation for atrial fibrillation: the ODIn-AF trial

Author

Schrickel, Jan Wilko, Beiert, Thomas, Linhart, Markus, Luetkens, Julian A., Schmitz, Jennifer, Schmid, Matthias, Hindricks, Gerhard, Arentz, Thomas, Stellbrink, Christoph, Deneke, Thomas, Bogossian, Harilaos, Sause, Armin, Steven, Daniel, Gonska, Bernd-Dieter, Rudic, Boris, Lewalter, Thorsten, Zabel, Markus, Geisler, Tobias, Schumacher, Burghard, Jung, Werner, Kleemann, Thomas, Luik, Armin, Veltmann, Christian, Coenen, Martin, and Nickenig, Georg

Published
2024
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15. Modelling the Historic Total Global Human Population

Author

Jean Marie Linhart

Abstract

The historic total global human population dataset is available on Wikipedia and provides an opportunity for modelling with simple models such as the exponential and logistic differential equations for population. Using the per-capita population growth rate (PPGR) predicted by these two models and estimated PPGR from the data, we are able to estimate parameters for the exponential model and discover that we cannot estimate parameters for the logistic model. However, we are able to create a new differential equation that models this data using ideas from the derivation of the logistic model. This is the superexponential model that goes to infinity in finite time. While the initial exponential and superexponential models are good for approximating the population data, neither really matches the PPGRs estimated from the data. We switch to a hybrid model that better matches the estimated PPGRs. It is superexponential for the first portion of the data and logistic for the rest. This hybrid model greatly reduces the modelling error and can extrapolate from the data. We note that the model switches between superexponential and logistic around 1960, the year the FDA-approved oral contraceptives, a fascinating historical tie-in with our modelling.

Published
2024
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20. L-C2ST: Local Diagnostics for Posterior Approximations in Simulation-Based Inference

Author

Linhart, Julia, Gramfort, Alexandre, and Rodrigues, Pedro L. C.

Subjects
Statistics - Machine Learning, Computer Science - Artificial Intelligence, Computer Science - Machine Learning, Quantitative Biology - Neurons and Cognition
Abstract

Many recent works in simulation-based inference (SBI) rely on deep generative models to approximate complex, high-dimensional posterior distributions. However, evaluating whether or not these approximations can be trusted remains a challenge. Most approaches evaluate the posterior estimator only in expectation over the observation space. This limits their interpretability and is not sufficient to identify for which observations the approximation can be trusted or should be improved. Building upon the well-known classifier two-sample test (C2ST), we introduce L-C2ST, a new method that allows for a local evaluation of the posterior estimator at any given observation. It offers theoretically grounded and easy to interpret -- e.g. graphical -- diagnostics, and unlike C2ST, does not require access to samples from the true posterior. In the case of normalizing flow-based posterior estimators, L-C2ST can be specialized to offer better statistical power, while being computationally more efficient. On standard SBI benchmarks, L-C2ST provides comparable results to C2ST and outperforms alternative local approaches such as coverage tests based on highest predictive density (HPD). We further highlight the importance of local evaluation and the benefit of interpretability of L-C2ST on a challenging application from computational neuroscience., Comment: 27 pages, 6 figures, 3 tables, 6 appendices, NeurIPS 2023

Published
2023

21. Optical markers of magnetic phase transition in CrSBr

Author

Linhart, W. M., Rybak, M., Birowska, M., Mosina, K., Mazanek, V., Scharoch, P., Kaczorowski, D., Sofer, Z., and Kudrawiec, R.

Subjects
Condensed Matter - Materials Science, Physics - Applied Physics
Abstract

Here, we investigate the role of the interlayer magnetic ordering of CrSBr in the framework of $\textit{ab initio}$ calculations and by using optical spectroscopy techniques. These combined studies allow us to unambiguously determine the nature of the optical transitions. In particular, photoreflectance measurements, sensitive to the direct transitions, have been carried out for the first time. We have demonstrated that optically induced band-to-band transitions visible in optical measurement are remarkably well assigned to the band structure by the momentum matrix elements and energy differences for the magnetic ground state (A-AFM). In addition, our study reveals significant differences in electronic properties for two different interlayer magnetic phases. When the magnetic ordering of A-AFM to FM is changed, the crucial modification of the band structure reflected in the direct-to-indirect band gap transition and the significant splitting of the conduction bands along the $\Gamma-Z$ direction are obtained. In addition, Raman measurements demonstrate a splitting between the in-plane modes $B^2_{2g}$/$B^2_{3g}$, which is temperature dependent and can be assigned to different interlayer magnetic states, corroborated by the DFT+U study. Moreover, the $B^2_{2g}$ mode has not been experimentally observed before. Finally, our results point out the origin of interlayer magnetism, which can be attributed to electronic rather than structural properties. Our results reveal a new approach for tuning the optical and electronic properties of van der Waals magnets by controlling the interlayer magnetic ordering in adjacent layers., Comment: 33 pages, 15 figures

Published
2023

23. Validation Diagnostics for SBI algorithms based on Normalizing Flows

Author

Linhart, Julia, Gramfort, Alexandre, and Rodrigues, Pedro L. C.

Subjects
Statistics - Machine Learning, Computer Science - Artificial Intelligence, Computer Science - Machine Learning, Quantitative Biology - Quantitative Methods
Abstract

Building on the recent trend of new deep generative models known as Normalizing Flows (NF), simulation-based inference (SBI) algorithms can now efficiently accommodate arbitrary complex and high-dimensional data distributions. The development of appropriate validation methods however has fallen behind. Indeed, most of the existing metrics either require access to the true posterior distribution, or fail to provide theoretical guarantees on the consistency of the inferred approximation beyond the one-dimensional setting. This work proposes easy to interpret validation diagnostics for multi-dimensional conditional (posterior) density estimators based on NF. It also offers theoretical guarantees based on results of local consistency. The proposed workflow can be used to check, analyse and guarantee consistent behavior of the estimator. The method is illustrated with a challenging example that involves tightly coupled parameters in the context of computational neuroscience. This work should help the design of better specified models or drive the development of novel SBI-algorithms, hence allowing to build up trust on their ability to address important questions in experimental science., Comment: 7 pages, 2 figures, 1 appendix, published at "Machine Learning and the Physical Sciences" workshop (NeurIPS 2022): https://ml4physicalsciences.github.io/2022/

Published
2022

24. Misprocessing of Alpha-Galactosidase A, Endoplasmic Reticulum Stress, and the Unfolded Protein Response

Author

Živná, Martina, Dostálová, Gabriela, Barešová, Veronika, Mušálková, Dita, Svojšová, Klára, Meiseles, Doria, Kinstlinger, Sara, Kuchař, Ladislav, Asfaw, Befekadu, Poupětová, Helena, Vlášková, Hana, Kmochová, Tereza, Vyleťal, Petr, Hartmannová, Hana, Hodaňová, Kateřina, Stránecký, Viktor, Steiner-Mrázová, Lenka, Hnízda, Aleš, Živný, Jan, Radina, Martin, Votruba, Miroslav, Sovová, Jana, Trešlová, Helena, Stolnaja, Larisa, Reková, Petra, Roblová, Lenka, Honsová, Eva, Rychlík, Ivan, Dvela-Levitt, Moran, Bleyer, Anthony J., Linhart, Aleš, Sikora, Jakub, and Kmoch, Stanislav

Published
2024
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31. Effects of multiple hormonal stimulation and stripping during out-of-spawning season on sperm quality of common carp Cyprinus carpio

Author

Mohammad Abdul Momin Siddique, Nururshopa Eskander Shazada, Songpei Zhang, Otomar Linhart, and Serhii Boryshpolets

Subjects
Hormonal stimulation, multiple strippings, Sperm motility, Ionic composition, Seminal plasma, Osmolality, Aquaculture. Fisheries. Angling, SH1-691
Abstract

The availability of mature broodstock that produces high-quality gametes is one of the vital issues with fish reproduction. The effects of multiple hormonal stimulations and continuous stripping of the same individual males on spermatozoa quality are unclear. Thus, this study aimed to investigate motility parameters and seminal plasma compositions of common carp sperm during out-of-spawning continuous stripping stimulated by multiple hormonal injections. Five mature males ∼3 years old, each approximately 1.7–2.3 kg bodyweight cultured in RAS at a stable temperature of 21 °C were used in this study. Fish were treated monthly (at the beginning of each month from August to October) with carp pituitary at 1.5 mg kg−1 (b.w.) dissolved in 0.9 % (w/v) NaCl solution 24 h before milt collection. The mean sperm concentration ranged from 17.55 to 20.19 × 109 mL−1 collected during the experiments and did not significantly vary among the sampling months (F = 2.352, p = 0.1374). However, the repeated measures ANOVA showed significant effects of sampling months (F = 25.24, p = 0.0001) and individual males (F = 7.50, p = 0.0001) on the motility parameters and seminal plasma compositions, but their interaction effects were not significant (F = 1.31, p = 0.079). One-way ANOVA revealed a significant difference in spermatozoa motility (F = 10.51, p = 0.0001) and pH of the seminal plasma (F = 90.00, p = 0.0001), but did not differ in curvilinear velocity (VCL), straight-line velocity (VSL), and ionic compositions (Na+, K+, Cl-, Ca2+, total protein, and osmolality) of the seminal plasma (p > 0.05). The mean spermatozoa motility in August (88.51–94.05 %) and September (89.88–96.00 %) was significantly higher than in October (83.99–89.58 %), but spermatozoa motility was >80 % in all males for the three consecutive months. The present study indicated that multiple hormonal stimulation and continuous stripping did not suppress common carp's spermatozoa production and quality parameters.

Published
2024
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32. Adult mortality from non-communicable diseases in Fiji's major ethnic groups 2013–17

Author

Catherine Dearie, Christine Linhart, Carah Figueroa, Varanisese Saumaka, Timothy Dobbins, Stephen Morrell, and Richard Taylor

Subjects
Sustainable development goals, Cause of death, Non-communicable disease, Fiji, Mortality, Probability of dying, Infectious and parasitic diseases, RC109-216
Abstract

Background: Sustainable Development Goal 3.4.1 (SDG3.4.1) targets a one-third reduction in non-communicable disease (NCD) mortality in ages 30–69-years by 2030 (relative to 2015). Directing interventions to achieve this aim requires reliable estimates of underlying cause of death (UCoD). This may be problematic when both cardiovascular diseases (CVD) and diabetes are present due to a lack of consistency in certification of such deaths. We estimate empirically 2013–17 NCD mortality in Fiji, by sex and ethnicity, from CVD, diabetes, cancer, and chronic lower respiratory diseases (CRD), and aggregated as NCD4. Methods: UCoD was determined from Medical Certificates of Cause-of-Death (MCCD) from the Fiji Ministry of Health after pre-processing of mortality data where diabetes and/or hypertension were present in order to generate internationally comparable UCoD. If no potentially fatal complications from diabetes or hypertension accompanied these causes in Part I (direct cause) of the MCCD, these conditions were re-assigned to Part II (contributory cause). The probability of a 30-year-old dying before reaching age 70-years (PoD30–70), by cause, was calculated. Findings: The PoD30–70 from NCD4 over 2013–17 differed by sex and ethnicity: in women, it was 36% (95%CI 35–37%) in i-Taukei and 27% (26–28%) in Fijians of Indian descent (FID); in men, it was 41% (40–42%) in both i-Taukei and FID.PoD30–70 from CVD, diabetes, cancer and CRD in women was: 18%, 10%, 13% and 1·0% in i-Taukei; 13%, 10%, 5·6% and 1·1% in FID; in men was: 28%, 8.4%, 7·6% and 2·2% in i-Taukei; 31%, 8.3%, 3.5% and 3·1% in FID. Interpretation: To achieve SDG3.4.1 goals in Fiji by 2030, effective population wide and ethnic-specific interventions targeting multiple NCDs are required to reduce PoD30–70 from NCD4: from 36% to 24% in i-Taukei, and 27% to 18% in FID women; and from 41% to 27% in i-Taukei and FID men. Funding: Not applicable.

Published
2024
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33. Improving the timeliness of birth registration in Fiji through a financial incentive

Author

Christine Linhart, Neel Singh, Meli Nadakuca, Varanisese Saumaka, Carlie Congdon, Sharita Serrao, Richard Taylor, and Stephen Morrell

Subjects
Fiji, Birth registration, Timeliness, Financial incentive, Ethnicity, Adolescent, Infectious and parasitic diseases, RC109-216
Abstract

Background: Fiji is a Pacific Island nation with the predominant ethnic groups indigenous Fijians (iTaukei) (62 %) and Fijians of Indian descent (31 %). This study reports on the effect of a Parental Assistance Payment Program (PAPP) tied to on-time birth registration, available in Fiji from August 2018 to July 2020. Methods: Unit record birth registration data (n = 117,829) for children born during 2016–22 were used to calculate mean birth-to-registration intervals and the likelihood of on-time birth registration (within 365 days) before the PAPP (January 2016–July 2018) compared to during the PAPP (August 2018–July 2020), by population disaggregations (sex, ethnicity, age, marital status). Results: During the PAPP, mean birth-to-registration intervals declined sharply by 81 %, from 665 days (95 %CI: 658–671) to 124 days (121–127). The largest declines were among i-Taukei children (803 to 139 days, 83 %) compared to non-iTaukei (283 to 76 days, 73 %); mothers aged 10–19 years (880 to 134 days, 85 %) compared to ≥20 years (653 to 123 days, 81 %); and single mothers (983 to 145 days, 85 %) compared to married mothers (570 to 115 days, 80 %). On-time birth registration increased from 57 % to 93 %, and the adjusted hazard ratio showed children born during the PAPP were 2.3 times more likely (95 %CI: 2.2–2.4) to have their birth registered on-time compared to children born before the PAPP. When the PAPP was discontinued in August 2020, the birth-to-registration interval increased sharply in all population groups. Conclusions: During the two-year period the PAPP was available, it was highly effective at improving the timeliness of birth registration, particularly among iTaukei children, young mothers, and single mothers. After the PAPP was discontinued, the timeliness of birth registration deteriorated sharply. Longer post-PAPP follow-up time (≠5 years) is required to determine whether the timeliness of birth registration has deteriorated to levels similar to those during the pre-PAPP period.

Published
2024
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34. The endocannabinoid ARA-S facilitates the activation of cardiac Kv7.1/KCNE1 channels from different species

Author

Irene Hiniesto-Iñigo, Veronika A. Linhart, Ali S. Kusay, and Sara I. Liin

Subjects
Electrophysiology, IKs, KCNQ1, lipid, Therapeutics. Pharmacology, RM1-950, Physiology, QP1-981
Abstract

The endogenous endocannabinoid-like compound N-arachidonoyl-L-serine (ARA-S) facilitates activation of the human Kv7.1/KCNE1 channel and shortens a prolonged action potential duration and QT interval in guinea pig hearts. Hence, ARA-S is interesting to study further in cardiac models to explore the functional impact of such Kv7.1/KCNE1-mediated effects. To guide which animal models would be suitable for assessing ARA-S effects, and to aid interpretation of findings in different experimental models, it is useful to know whether Kv7.1/KCNE1 channels from relevant species respond similarly to ARA-S. To this end, we used the two-electrode voltage clamp technique to compare the effects of ARA-S on Kv7.1/KCNE1 channels from guinea pig, rabbit, and human Kv7.1/KCNE1, when expressed in Xenopus laevis oocytes. We found that the activation of Kv7.1/KCNE1 channels from all tested species was facilitated by ARA-S, seen as a concentration-dependent shift in the voltage-dependence of channel opening and increase in current amplitude and conductance over a broad voltage range. The rabbit channel displayed quantitatively similar effects as the human channel, whereas the guinea pig channel responded with more prominent increase in current amplitude and maximal conductance. This study suggests that rabbit and guinea pig models are both suitable for studying ARA-S effects mediated via Kv7.1/KCNE1.

Published
2024
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35. Search for central exclusive production of top quark pairs in proton-proton collisions at s $$ \sqrt{s} $$ = 13 TeV with tagged protons

Author

The CMS collaboration, A. Tumasyan, W. Adam, J. W. Andrejkovic, T. Bergauer, S. Chatterjee, K. Damanakis, M. Dragicevic, A. Escalante Del Valle, P. S. Hussain, M. Jeitler, N. Krammer, L. Lechner, D. Liko, I. Mikulec, P. Paulitsch, F. M. Pitters, J. Schieck, R. Schöfbeck, D. Schwarz, S. Templ, W. Waltenberger, C.-E. Wulz, M. R. Darwish, T. Janssen, T. Kello, H. Rejeb Sfar, P. Van Mechelen, E. S. Bols, J. D’Hondt, A. De Moor, M. Delcourt, H. El Faham, S. Lowette, S. Moortgat, A. Morton, D. Müller, A. R. Sahasransu, S. Tavernier, W. Van Doninck, D. Vannerom, B. Clerbaux, G. De Lentdecker, L. Favart, D. Hohov, J. Jaramillo, K. Lee, M. Mahdavikhorrami, I. Makarenko, A. Malara, S. Paredes, L. Pétré, N. Postiau, E. Starling, L. Thomas, M. Vanden Bemden, C. Vander Velde, P. Vanlaer, D. Dobur, J. Knolle, L. Lambrecht, G. Mestdach, M. Niedziela, C. Rendón, C. Roskas, A. Samalan, K. Skovpen, M. Tytgat, N. Van Den Bossche, B. Vermassen, L. Wezenbeek, A. Benecke, G. Bruno, F. Bury, C. Caputo, P. David, C. Delaere, I. S. Donertas, A. Giammanco, K. Jaffel, Sa. Jain, V. Lemaitre, K. Mondal, J. Prisciandaro, A. Taliercio, T. T. Tran, P. Vischia, S. Wertz, G. A. Alves, E. Coelho, C. Hensel, A. Moraes, P. Rebello Teles, W. L. Aldá Júnior, M. Alves Gallo Pereira, M. Barroso Ferreira Filho, H. Brandao Malbouisson, W. Carvalho, J. Chinellato, E. M. Da Costa, G. G. Da Silveira, D. De Jesus Damiao, V. Dos Santos Sousa, S. Fonseca De Souza, J. Martins, C. Mora Herrera, K. Mota Amarilo, L. Mundim, H. Nogima, A. Santoro, S. M. Silva Do Amaral, A. Sznajder, M. Thiel, F. Torres Da Silva De Araujo, A. Vilela Pereira, C. A. Bernardes, L. Calligaris, T. R. Fernandez Perez Tomei, E. M. Gregores, P. G. Mercadante, S. F. Novaes, Sandra S. Padula, A. Aleksandrov, R. Hadjiiska, P. Iaydjiev, M. Misheva, M. Rodozov, M. Shopova, G. Sultanov, A. Dimitrov, T. Ivanov, L. Litov, B. Pavlov, P. Petkov, A. Petrov, E. Shumka, T. Cheng, T. Javaid, M. Mittal, L. Yuan, M. Ahmad, G. Bauer, Z. Hu, S. Lezki, K. Yi, G. M. Chen, H. S. Chen, M. Chen, F. Iemmi, C. H. Jiang, A. Kapoor, H. Liao, Z.-A. Liu, V. Milosevic, F. Monti, R. Sharma, J. Tao, J. Thomas-Wilsker, J. Wang, H. Zhang, J. Zhao, A. Agapitos, Y. An, Y. Ban, C. Chen, A. Levin, C. Li, Q. Li, X. Lyu, Y. Mao, S. J. Qian, X. Sun, D. Wang, J. Xiao, H. Yang, J. Li, M. Lu, Z. You, X. Gao, D. Leggat, H. Okawa, Y. Zhang, Z. Lin, C. Lu, M. Xiao, C. Avila, D. A. Barbosa Trujillo, A. Cabrera, C. Florez, J. Fraga, J. Mejia Guisao, F. Ramirez, M. Rodriguez, J. D. Ruiz Alvarez, D. Giljanovic, N. Godinovic, D. Lelas, I. Puljak, Z. Antunovic, M. Kovac, T. Sculac, V. Brigljevic, B. K. Chitroda, D. Ferencek, D. Majumder, M. Roguljic, A. Starodumov, T. Susa, A. Attikis, K. Christoforou, G. Kole, M. Kolosova, S. Konstantinou, J. Mousa, C. Nicolaou, F. Ptochos, P. A. Razis, H. Rykaczewski, H. Saka, M. Finger, A. Kveton, E. Ayala, E. Carrera Jarrin, S. Elgammal, A. Ellithi Kamel, M. A. Mahmoud, Y. Mohammed, S. Bhowmik, R. K. Dewanjee, K. Ehataht, M. 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Krasnikov, E. Kuznetsova, A. Lanev, P. Levchenko, A. Litomin, O. Lukina, N. Lychkovskaya, V. Makarenko, A. Malakhov, V. Matveev, V. Murzin, A. Nikitenko, S. Obraztsov, V. Okhotnikov, I. Ovtin, V. Palichik, P. Parygin, V. Perelygin, M. Perfilov, G. Pivovarov, V. Popov, E. Popova, O. Radchenko, V. Rusinov, M. Savina, V. Savrin, D. Selivanova, V. Shalaev, S. Shmatov, S. Shulha, Y. Skovpen, S. Slabospitskii, V. Smirnov, D. Sosnov, A. Stepennov, V. Sulimov, A. Terkulov, O. Teryaev, I. Tlisova, M. Toms, A. Toropin, L. Uvarov, A. Uzunian, E. Vlasov, P. Volkov, A. Vorobyev, N. Voytishin, B. S. Yuldashev, A. Zarubin, I. Zhizhin, A. Zhokin, The TOTEM collaboration, G. Antchev, P. Aspell, I. Atanassov, V. Avati, J. Baechler, C. Baldenegro Barrera, V. Berardi, M. Berretti, V. Borshch, E. Bossini, U. Bottigli, M. Bozzo, H. Burkhardt, F. S. Cafagna, M. G. Catanesi, M. Deile, F. De Leonardis, M. Doubek, D. Druzhkin, K. Eggert, V. Eremin, A. Fiergolski, F. Garcia, V. Georgiev, S. Giani, L. Grzanka, J. Hammerbauer, T. Isidori, V. Ivanchenko, M. Janda, A. Karev, J. Kašpar, B. Kaynak, J. Kopal, V. Kundrát, S. Lami, R. Linhart, C. Lindsey, M. V. Lokajíček, L. Losurdo, F. Lucas Rodríguez, M. Macrí, M. Malawski, N. Minafra, S. Minutoli, K. Misan, T. Naaranoja, F. Nemes, H. Niewiadomski, E. Oliveri, F. Oljemark, M. Oriunno, K. Österberg, S. Ozkorucuklu, P. Palazzi, V. Passaro, Z. Peroutka, O. Potok, J. Procházka, M. Quinto, E. Radermacher, E. Radicioni, F. Ravotti, C. Royon, G. Ruggiero, H. Saarikko, V. D. Samoylenko, A. Scribano, J. Široký, J. Smajek, W. Snoeys, R. Stefanovitch, C. Taylor, E. Tcherniaev, N. Turini, O. Urban, V. Vacek, O. Vavroch, J. Welti, J. Williams, and J. Zich

Subjects
Hadron-Hadron Scattering, Top Physics, Nuclear and particle physics. Atomic energy. Radioactivity, QC770-798
Abstract

Abstract A search for the central exclusive production of top quark-antiquark pairs ( t t ¯ $$ \textrm{t}\overline{\textrm{t}} $$ ) is performed for the first time using proton-tagged events in proton-proton collisions at the LHC at a centre-of-mass energy of 13 TeV. The data correspond to an integrated luminosity of 29.4 fb −1. The t t ¯ $$ \textrm{t}\overline{\textrm{t}} $$ decay products are reconstructed using the central CMS detector, while forward protons are measured in the CMS-TOTEM precision proton spectrometer. An observed (expected) upper bound on the production cross section of 0.59 (1.14) pb is set at 95% confidence level, for collisions of protons with fractional momentum losses between 2 and 20%.

Published
2024
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36. Long‐term outcomes and reverse remodelling in recently diagnosed unexplained left ventricular systolic dysfunction

Author

Petr Kuchynka, Jana Podzimkova, Josef Marek, Barbara Anna Danek, Ivana Vitkova, Miluse Kreidlova, Lenka Roblova, Tomas Kovarnik, Stanislav Simek, Jan Horak, Jan Habasko, Ales Linhart, and Tomas Palecek

Subjects
Dilated cardiomyopathy, Endomyocardial biopsy, Left ventricular systolic dysfunction, Mortality, Reverse remodelling, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Abstract Aims In patients with recently diagnosed non‐ischaemic LV systolic dysfunction, left ventricular reverse remodelling (LVRR) and favourable prognosis has been documented in studies with short‐term follow‐up. The aim of our study was to assess the long‐term clinical course and stability of LVRR in these patients. Methods and results We prospectively studied 133 patients (37 women; 55 [interquartile range 46, 61] years) with recently diagnosed unexplained LV systolic dysfunction, with heart failure symptoms lasting

Published
2024
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37. Anderson–Fabry Disease Homozygosity: Rare Case of Late-Onset Variant

Author

Gabriela Dostalova, Jaroslav Januska, Michaela Veselá, Petra Reková, Anna Taborska, Martin Pleva, David Zemanek, and Aleš Linhart

Subjects
case report, Anderson–Fabry disease, homozygosity, exon 5, late onset, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Anderson–Fabry Disease (AFD) is a rare, X-linked lysosomal storage disorder caused by a mutation in the α-Galactosidase A gene resulting in α-Galactosidase A enzyme (α-Gal A) deficiency. The metabolic defect leads to the progressive accumulation of glycosphingolipids and the structural and functional impairment of affected organs. Due to the inheritance pattern, male patients are hemizygous with more severe manifestations of the disease as compared to females who, in most cases, are heterozygous with delayed and variable clinical presentation caused by uneven X-chromosome inactivation. Fabry disease cases are often identified by targeted screening programs in high-risk groups, such as in patients with end-stage renal disease, premature stroke, or unexplained cardiomyopathy. Here, we describe a unique case of a homozygous female patient identified by a nationwide screening program in hypertrophic cardiomyopathy patients. Before the systematic screening, the patient had a diagnosis of hypertrophic obstructive cardiomyopathy and was treated accordingly, including with alcohol septal ablation to reduce the obstructive gradient. The confirmation of Fabry disease led to the discovery of the same variant in several members of her family. The identified variant was c.644A>G, p.Asn215Ser (p.N215S), which is known to cause predominant cardiac involvement with late onset of the disease. This variant is amenable to oral therapy with the small-molecule chaperone migalastat, which was started and then interrupted due to the recurrence of the patient’s migraine and then re-initiated again after two years. During this period, the patient received enzyme replacement therapy with agalsidase beta but developed progressively worsening venous access. Our case illustrates the importance of the systematic screening of patients with clinical evidence of hypertrophic cardiomyopathy in whom the routine diagnostic process fails to discover Fabry disease, in particular variants with late-onset cardiac manifestations. Many of the late-onset variants are amenable to orally active therapy with migalastat, which significantly improves the comfort of the treatment. Its long-term results are being analyzed by a large international “Follow-me” registry, which was designed to verify the validity of pivotal trials with migalastat in Fabry disease.

Published
2024
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40. New Data Indicate Larger Decline in Morphological Diversity in Split-Footed Lacewing Larvae than Previously Estimated

Author

Laura Buchner, Simon Linhart, Florian Braig, Gideon T. Haug, Thomas Weiterschan, Carolin Haug, and Joachim T. Haug

Subjects
biodiversity, Myanmar amber, Neuroptera, Nymphidae, quantitative morphology, Science
Abstract

Modern insect decline sparks interest in similar declines of the past. Neuroptera, the group of lacewings, has been suggested to have undergone decline after the Cretaceous, and quantitative studies of larval morphology have supported this view. One of the groups within Neuroptera seeing a major decline is that of split-footed lacewings, Nymphidae. We here report 13 new larval specimens of split-footed lacewings from about 100-million-year-old Kachin amber, Myanmar. We explore how enlarging the data set to 60 specimens and expanding the investigated morphological structures affect the recognition of decline. The expanded data set has an increased morphospace, indicating a lack of saturation. The decline is, therefore, likely even larger than so far anticipated for Nymphidae. The study of head and mouthparts provides the strongest signal for a loss of diversity, which is feasible due to the direct coupling to feeding ecology. Analysis of the trunk region cannot recover a signal for loss of diversity. Sampling issues play a role here: the trunk of the larvae is less often well preserved, and the fossil larvae are more likely in early developmental stages due to the constraints of preservation.

Published
2025
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42. Fully Automated Artificial Intelligence Solution for Human Epidermal Growth Factor Receptor 2 Immunohistochemistry Scoring in Breast Cancer: A Multireader Study

Author

Krishnamurthy, Savitri, Schnitt, Stuart J., Vincent-Salomon, Anne, Canas-Marques, Rita, Colon, Eugenia, Kantekure, Kanchan, Maklakovski, Marina, Finck, Wilfrid, Thomassin, Jeanne, Globerson, Yuval, Bien, Lilach, Mallel, Giuseppe, Grinwald, Maya, Linhart, Chaim, Sandbank, Judith, and Vecsler, Manuela

Published
2024
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43. Predictors of Clinical Success of Cardioneuroablation in Patients With Syncope: Results of a Multicenter Study

Author

Barrio-Lopez, María Teresa, Álvarez-Ortega, Carlos, Minguito-Carazo, Carlos, Franco, Eduardo, García-Granja, Pablo Elpidio, Alcalde-Rodríguez, Óscar, Salvador-Montañés, Óscar, Francisco-Pascual, Jaume, Macías-Ruíz, Rosa, Marco Del Castillo, Álvaro, Giacoman-Hernández, Sebastián, Expósito-García, Víctor, Garcia-Izquierdo, Eusebio, Manuel Durán, Juan, Calvo-Galiano, Naiara, Luis Ibáñez-Criado, José, García-Cuenca, Enrique, Calero, Sofia, Fernandez-Portales, Javier, Linhart, Markus, Rodriguez-Mañero, Moises, Martínez-Alday, Jesús Daniel, Sanchez-Quintana, Damian, Almendral-Garrote, Jesús, and Moya-Mitjáns, Ángel

Published
2024
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46. RATTUS (Rat Thoracic Ultrasound): diagnosis of pneumothorax in pet rats

Author

A. Piskovská, K. Kraszewska, K. Hauptman, J. Chloupek, P. Linhart, and V. Jekl

Subjects
rat, RATTUS, pneumothorax, thoracic disease, respiratory disorders, dyspnoea, Veterinary medicine, SF600-1100
Abstract

IntroductionRat thoracic ultrasound (RATTUS) is a non-invasive, easy-to-perform method for the evaluation of the pleural space and lungs in pet rats. The aim of the article is to present species-specific differences in the sonographic diagnosis of pneumothorax (PTX) in pet rats.MethodsIn total, 158 client-owned pet rats were examined during the period from July 2023 to January 2024. PTX was diagnosed in 20 of the examined rats (13.25%, the age of the animals ranged from 2 months to 32 months (19.08 ± 6.93 months; mean ± SD) and their body weight ranged from 97 g to 885 g (461.27 ± 138.97 g; mean ± SD). Radiographic confirmation of PTX was performed in all these 20 rats, in the control group radiography was used to confirm that PTX was not present.ResultsThe lung point and the barcode sign was found in 7/20 animals with sensitivity of 33.3% (95% CI, 0.16–0.59) and specificity of 100% (95% CI, 0.97–1.0). The abnormal curtain sign was found in 19/20 of animals with the sensitivity of 95% (95% CI, 0.73–0.99.7) and the specificity of 89% (95% CI, 0.82–0.93). The abnormalities in the substernal access were in 17/20 of animals with the sensitivity of 85% (95% CI, 0.61–0.96) and the specificity of 71% (95% CI, 0.62–0.78).DiscussionIn conclusion, RATTUS is a non-invasive method for the diagnosis of PTX in rats. Lung point and barcode sign are specific but not easily diagnosed signs. The curtain sign in RATTUS is not specific for PTX, as there are e.g. geriatric rats (rats older than 1,5 years) in which the abnormal curtain sign is visible without the presence of PTX. The presence of moderate to severe PTX can be assessed by the substernal approach based on the presence of cardiac displacement toward the collapsed lung lobe, and on evaluation of the lung inflation symmetry. This sign is not specific for PTX but in conjunction with other ultrasonic signs described makes the RATTUS a feasible tool for PTX diagnosis in rats.

Published
2024
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47. Optimizing extenders for short-term storage of Sterlet (Acipenser ruthenus) sperm

Author

Nururshopa Eskander Shazada, Songpei Zhang, Mohammad Abdul Momin Siddique, Yu Cheng, Marek Rodina, Sayyed Mohammad Hadi Alavi, and Otomar Linhart

Subjects
CASA, Seminal plasma, Spermatozoa motility, Spermatozoa velocity, Sturgeon, Aquaculture. Fisheries. Angling, SH1-691
Abstract

Considering endangered fish, storage of sterlet (Acipenser ruthenus) gamete is crucial, and investigating the most suitable extender for short-term storage of sperm is necessary. Therefore, the present study aimed to optimize suitable extenders for short-term storage of sterlet spermatozoa and determine the effects of storage periods and different extenders on spermatozoa motility parameters. The sperm of five mature males with good spermatozoa motility (∼80 %) were diluted with 20 different extenders having various Na+ and K+ concentrations and osmolality. Spermatozoa motility performances were assessed using a CASA system within 144 h storage at 0–2 °C. Undiluted sperm was used as a control. Seminal plasma Na+, K+, Ca2+ and Cl- concentrations were 17.56±10.12, 2.48±1.14, 0.11±0.06, and 6.20±3.42 mmol/L with osmolality of 35.60±20.70 mOsm/kg. A two-way ANOVA showed significant effects of storage time, extender, and their interaction on spermatozoa motility, curvilinear velocity (VCL), and straight-line velocity (VSL) (p3 mM resulted in lower spermatozoa motility performance. When the effects of storage time were studied, spermatozoa motility, VCL, and VSL in non-diluted sperm and those diluted with E18-E20 were decreased at 24–48 h and 72–96 h post-storage, respectively. This study shows that extenders with higher osmolality (39–62 mOsm/kg) and lower K+ (1 mmol/L) are the most suitable for storing sterlet sperm for a short period.

Published
2024
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48. Pulmonary perfusion in long‐term survivors of COVID‐19‐related severe acute respiratory distress syndrome treated by extracorporeal membrane oxygenation

Author

Lucie Miksová, Vladimír Dytrych, Václav Ptáčník, Martin Balík, Aleš Linhart, Jan Bělohlávek, and Pavel Jansa

Subjects
chronic thromboembolic pulmonary hypertension, COVID‐19 infection, extracorporeal membrane oxygenation, pulmonary perfusion, venous thromboembolic events, Diseases of the circulatory (Cardiovascular) system, RC666-701, Diseases of the respiratory system, RC705-779
Abstract

Abstract COVID‐19 associates with a hypercoagulant state and an increased risk for venous thromboembolic events (VTEs). Whether severe COVID‐19 infection requiring extracorporeal membrane oxygenation (ECMO) support might lead to chronic pulmonary perfusion abnormalities and chronic thromboembolic pulmonary disease/hypertension remains unclear. The purpose of this study was to evaluate chronic pulmonary perfusion abnormalities in long‐term survivors of COVID‐19‐related severe acute respiratory distress syndrome (ARDS) treated by ECMO at our institution. Pulmonary perfusion was examined by ventilation/perfusion (V/Q) single‐photon emission computed tomography or V/Q planar scintigraphy at least 3 months after ECMO explantation, comorbidities and incidence of thromboembolic events were recorded as well. Of 172 COVID‐19 patients treated by ECMO for severe COVID‐19 pneumonia between March 2020 and November 2021, only 80 were successfully weaned from ECMO. Of those, 37 patients were enrolled into the present analysis (27% female, mean age 52 years). Median duration of ECMO support was 12 days. In 24 (65%) patients VTE was recorded in the acute phase (23 patients developed ECMO cannula‐related deep vein thrombosis, 5 of them had also a pulmonary embolism, and one thrombus was associated with a central catheter). The median duration between ECMO explantation and assessment of pulmonary perfusion was 420 days. No segmental or larger mismatched perfusion defects were then detected in any patient. In conclusion, in long‐term survivors of COVID‐19‐related ARDS treated by ECMO, no persistent pulmonary perfusion abnormalities were detected although VTE was common.

Published
2024
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49. Characterisation of the dip-bump structure observed in proton-proton elastic scattering at $\sqrt s$ = 8 TeV

Author

The TOTEM Collaboration, Antchev, G., Aspell, P., Atanassov, I., Avati, V., Baechler, J., Barrera, C. Baldenegro, Berardi, V., Berretti, M., Borchsh, V., Bossini, E., Bottigli, U., Bozzo, M., Burkhardt, H., Cafagna, F. S., Catanesi, M. G., Csanád, M., Csörgő, T., Deile, M., De Leonardis, F., Doubek, M., Druzhkin, D., Eggert, K., Eremin, V., Ferro, F., Fiergolski, A., Forthomme, L., Garcia, F., Georgiev, V., Giani, S., Grzanka, L., Hammerbauer, J., Isidori, T., Ivanchenko, V., Janda, M., Karev, A., Kašpar, J., Kaynak, B., Kopal, J., Kundrát, V., Lami, S., Latino, G., Linhart, R., Lindsey, C., Lokajíček, M. V., Losurdo, L., Rodríguez, F. Lucas, Macrí, M., Malawski, M., Minafra, N., Minutoli, S., Naaranoja, T., Nemes, F., Niewiadomski, H., Novák, T., Oliveri, E., Oljemark5, F., Oriunno, M., Österberg, K., Palazzi, P., Passaro, V., Peroutka, Z., Procházka, J., Quinto, M., Radermacher, E., Radicioni, E., Ravotti, F., Robutti, E., Royon, C., Ruggiero, G., Saarikko, H., Samoylenko, V. D., Scribano, A., Siroky, J., Smajek, J., Snoeys, W., Stefanovitch, R., Sziklai, J., Taylor, C., Tcherniaev, E., Turini, N., Urban, O., Vacek, V., Vavroch, O., Welti, J., Williams, J., Zich, J., and Zielinski, K.

Subjects
High Energy Physics - Experiment
Abstract

The TOTEM collaboration at the CERN LHC has measured the differential cross-section of elastic proton-proton scattering at $\sqrt{s} = 8\ {\rm TeV}$ in the squared four-momentum transfer range $0.2\ {\rm GeV^{2}} < |t| < 1.9\ {\rm GeV^{2}}$. This interval includes the structure with a diffractive minimum ("dip") and a secondary maximum ("bump") that has also been observed at all other LHC energies, where measurements were made. A detailed characterisation of this structure for $\sqrt{s} = 8\ {\rm TeV}$ yields the positions, $|t|_{\rm dip} = (0.521 \pm 0.007)\ {\rm GeV^2}$ and $|t|_{\rm bump} = (0.695 \pm 0.026)\ {\rm GeV^2}$, as well as the cross-section values, ${{\rm d}\sigma/{\rm d} t}_{\rm dip} = (15.1 \pm 2.5)\ {\rm{\mu b/GeV^2}}$ and ${{\rm d}\sigma/{\rm d} t}_{\rm bump} = (29.7 \pm 1.8)\ {\rm{\mu b/GeV^2}}$, for the dip and the bump, respectively.

Published
2021

50. Wannier Diagram and Brown-Zak Fermions of Graphene on Hexagonal Boron-Nitride

Author

Fabian, Thomas, Kausel, Matthias, Linhart, Lukas, Burgdörfer, Joachim, and Libisch, Florian

Subjects
Condensed Matter - Mesoscale and Nanoscale Physics
Abstract

The moir\'e potential of graphene on hexagonal boron nitride (hBN) generates a supercell sufficiently large as to thread a full magnetic flux quantum $\Phi_0$ for experimentally accessible magnetic field strengths. Close to rational fractions of $\Phi_0$, $p/q \cdot\Phi_0$, magnetotranslation invariance is restored giving rise to Brown-Zak fermions featuring the same dispersion relation as in the absence of the field. Employing a highly efficient numerical approach we have performed the first realistic simulation of the magnetoconductance for a 250 nm wide graphene ribbon on hexagonal boron nitride using a full ab-initio derived parametrization including strain. The resulting Hofstadter butterfly is analyzed in terms of a novel Wannier diagram for Landau spectra of Dirac particles that includes the lifting of the spin and valley degeneracy by the magnetic field and the moir\'e potential. This complex diagram can account for many experimentally observed features on a single-particle level, such as spin and valley degeneracy lifting and a non-periodicidy in $\Phi_0$., Comment: 6 pages, 4 figures

Published
2021
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