bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss-of-function variants inMYCBP2cause neurobehavioural phenotypes and corpus callosum defects
Authors: AlAbdi Lama , Desbois Muriel , Rusnac Domniţa-Valeria , Sulaiman Raashda A , Rosenfeld Jill A , Lalani Seema , Murdock David R , Burrage Lindsay C ,   Undiagnosed Diseases Network, Billie Au Ping Yee , Towner Shelley , Wilson William G , Wong Lawrence , Brunet Theresa , Strobl-Wildemann Gertrud , Burton Jennifer E , Hoganson George , McWalter Kirsty , Begtrup Amber , Zarate Yuri A , Christensen Elyse L , Opperman Karla J , Giles Andrew C , Helaby Rana , Kania Artur , Zheng Ning , Grill Brock , Alkuraya Fowzan S 
Published: October 2022

AbstractThe corpus callosum is a bundle of axon fibres that connects the two hemispheres of the brain. Neurodevelopmental disorders that feature dysgenesis of the corpus callosum as a core phenotype offer a valuable window into pathology derived from abnormal axon development. Here, we describe a cohort of eight patients with a neurodevelopmental disorder characterized by a range of deficits including corpus callosum abnormalities, developmental delay, intellectual disability, epilepsy and autistic features. Each patient harboured a distinct de novo variant in MYCBP2, a gene encoding an atypical really interesting new gene (RING) ubiquitin ligase and signalling hub with evolutionarily conserved functions in axon development. We used CRISPR/Cas9 gene editing to introduce disease-associated variants into conserved residues in the Caenorhabditis elegans MYCBP2 orthologue, RPM-1, and evaluated functional outcomes in vivo. Consistent with variable phenotypes in patients with MYCBP2 variants, C. elegans carrying the corresponding human mutations in rpm-1 displayed axonal and behavioural abnormalities including altered habituation. Furthermore, abnormal axonal accumulation of the autophagy marker LGG-1/LC3 occurred in variants that affect RPM-1 ubiquitin ligase activity. Functional genetic outcomes from anatomical, cell biological and behavioural readouts indicate that MYCBP2 variants are likely to result in loss of function. Collectively, our results from multiple human patients and CRISPR gene editing with an in vivo animal model support a direct link between MYCBP2 and a human neurodevelopmental spectrum disorder that we term, MYCBP2-related developmental delay with corpus callosum defects (MDCD).
The new 2022 ESC Guidelines on Cardio-oncology and their impact on the Acute Cardiovascular Care Society
Authors: von Kemp Berlinde , Halvorsen Sigrun , Nohria Anju 
Published: October 2022

Structured summaryIn this perspective piece on the recently published ESC Guidelines on Cardio-oncology and the Consensus Statements from the Acute Cardiovascular Care Association, we summarize key learning points regarding the management of acute cardiovascular disease in patients with cancer. This document outlines where other pre-existing ESC Guidelines can be applied to the management of acute cardiovascular disease in patients with cancer while simultaneously highlighting important gaps in knowledge that require further research.Cancer and cardiovascular disease share common risk factors and often co-exist, especially in older patients. In addition, patients with cancer undergoing active treatment are exposed to multiple, potentially cardiotoxic drugs, which may manifest as a variety of cardiovascular events, including left-ventricular systolic dysfunction and heart failure, arrhythmias, hypertension, or acute venous and arterial vascular events.Knowledge about potential causative cancer therapeutics is necessary for rapid recognition and management to improve cardiovascular outcomes and guide ongoing cancer treatment. Specifically, the importance of rapidly interrupting culprit cancer drugs is highlighted, as well as instituting standard guideline-based therapies for conditions such as acute heart failure and acute coronary syndromes [ST-elevation myocardial infarction and high-risk non-ST-elevation acute coronary syndrome (ACS)]. Given the high prevalence of thrombocytopenia and increased bleeding risk in patients with cancer, we are provided with platelet cut-offs for the use of different antiplatelet agents and anticoagulants for patients with ACS and atrial arrhythmias. In contrast, given the hypercoagulable milieu of cancer, we are provided information regarding types of anticoagulants, drug–drug interactions, and duration of anticoagulation in patients with acute venous thromboembolism, as well as for atrial fibrillation. They also discuss the diagnostic and treatment strategies for the unique cardiotoxicities seen with novel cancer therapeutics such as immune checkpoint inhibitors and chimeric receptor antigen T-cell therapy. Last, but not least, the authors emphasize that the care of these patients requires close collaboration between cardiology and oncology to maximize both cardiovascular and cancer outcomes.
Noncommunicating acute type A aortic dissection in elderly patients: Surgery versus medical management
Authors: Nakamae Kosuke , Oshitomi Takashi , Uesugi Hideyuki , Ideta Ichiro , Takaji Kentaro , Sassa Toshiharu , Murata Hidetaka , Hirota Masataka 
Published: October 2022

AbstractOBJECTIVESOur goal was to evaluate the surgical and conservative outcomes of acute type A aortic dissection with a thrombosed false lumen of the ascending aorta in elderly patients.METHODSPatients older than 75 years with acute type A aortic dissection admitted to our hospital from October 2011 to December 2020 were reviewed retrospectively, including those with the noncommunicating type without malperfusion and low physical capacity prehospitalization.RESULTSSixty-six patients were enrolled consecutively in the medical (M, n = 30) and surgical (S, n = 36) groups. The ascending aorta was the most replaced section in the S group (78%). Groups did not differ significantly in hospital deaths and in intensive care unit and hospital stays. Two patients (7%) underwent surgery and 3 (10%) underwent redissection in the M group. No significant difference existed between the groups in the decline of physical performance during hospitalization. Seven patients in the M group (24%) had aorta-related events in the late period as opposed to none in the S group (P=0.003). Survival rates after 4 years were 78.3% and 71.4% in the S and M groups, respectively (P=0.154). The cumulative incidence of overall reintervention due to an aortic event was significantly higher in the M group; however, the 2 groups did not differ significantly in overall aorta-related deaths.CONCLUSIONSSurgical outcomes of noncommunicating acute type A aortic dissection in elderly patients were favorable. There was no significant difference in maintaining physical function at discharge, and the medical group had a significantly higher overall aortic event rate than the surgical group.
CODE-EHR best practice framework for the use of structured electronic healthcare records in clinical research
Authors: Kotecha Dipak , Asselbergs Folkert W , Achenbach Stephan , Anker Stefan D , Atar Dan , Baigent Colin , Banerjee Amitava , Beger Birgit , Brobert Gunnar , Casadei Barbara , Ceccarelli Cinzia , Cowie Martin R , Crea Filippo , Cronin Maureen , Denaxas Spiros , Derix Andrea , Fitzsimons Donna , Fredriksson Martin , Gale Chris P , Gkoutos Georgios V , Goettsch Wim , Hemingway Harry , Ingvar Martin , Jonas Adrian , Kazmierski Robert , Løgstrup Susanne , Thomas Lumbers R , Lüscher Thomas F , McGreavy Paul , Piña Ileana L , Roessig Lothar , Steinbeisser Carl , Sundgren Mats , Tyl Benoît , van Thiel Ghislaine , van Bochove Kees , Vardas Panos E , Villanueva Tiago , Vrana Marilena , Weber Wim , Weidinger Franz , Windecker Stephan , Wood Angela , Grobbee Diederick E ,   the Innovative Medicines Initiative BigData@Heart Consortium, European Society of Cardiology, CODE-EHR international consensus group, Kurz Xavier , Concato John , Kazmierski Robert , Morales Jose Pablo , Piña Ileana , Goettsch Wim , Jonas Adrian , Hedberg Niklas , Crea Filippo , Lüscher Thomas F , Weber Wim , Villanueva Tiago , Spencer Stuart , Sarkar Rupa , Fredriksson Martin , Sundgren Mats , Derix Andrea , Brobert Gunnar , Roessig Lothar , Tyl Benoit , van Bochove Kees , Cronin Maureen , Carroll Colm , Thompson Ceri , Beger Birgit , Løgstrup Susanne , Vrana Marilena , McGreavy Paul , Casadei Barbara , Achenbach Stephan , Tursini Valentina , Vardas Panos E , Atar Dan , Baigent Colin , Gale Chris P , Fitzsimons Donna , Windecker Stephan , Anker Stefan D , Cowie Martin , Banerjee Amitava , Hemingway Harry , Lumbers R Tom , Denaxas Spiros , Asselbergs Folkert W , Grobbee Rick , Van Thiel Ghislaine , Kotecha Dipak , Gkoutos George V , Wood Angela , Ingvar Martin , Steinbeisser Carl , Petrova Ana , Ceccarelli Cinzia , Baljevic Katija , Vairami Polyxeni , Taylor Jennifer 
Published: October 2022

Abstract
Big data is central to new developments in global clinical science aiming to improve the lives of patients. Technological advances have led to the routine use of structured electronic healthcare records with the potential to address key gaps in clinical evidence. The covid-19 pandemic has demonstrated the potential of big data and related analytics, but also important pitfalls. Verification, validation, and data privacy, as well as the social mandate to undertake research are key challenges. The European Society of Cardiology and the BigData@Heart consortium have brought together a range of international stakeholders, including patient representatives, clinicians, scientists, regulators, journal editors and industry. We propose the CODE-EHR Minimum Standards Framework as a means to improve the design of studies, enhance transparency and develop a roadmap towards more robust and effective utilisation of healthcare data for research purposes.
Transcriptome analysis of FOXO-dependent hypoxia gene expression identifies Hipk as a regulator of low oxygen tolerance in Drosophila
Authors: Ding Kate , Barretto Elizabeth C , Johnston Michael , Lee Byoungchun , Gallo Marco , Grewal Savraj S 
Published: October 2022

Abstract
When exposed to low oxygen or hypoxia, animals must alter their metabolism and physiology to ensure proper cell-, tissue-, and whole-body level adaptations to their hypoxic environment. These alterations often involve changes in gene expression. While extensive work has emphasized the importance of the HIF-1 alpha transcription factor on controlling hypoxia gene expression, less is known about other transcriptional mechanisms. We previously identified the transcription factor FOXO as a regulator of hypoxia tolerance in Drosophila larvae and adults. Here, we use an RNA-sequencing approach to identify FOXO-dependent changes in gene expression that are associated with these tolerance effects. We found that hypoxia altered the expression of over 2,000 genes and that ∼40% of these gene expression changes required FOXO. We discovered that hypoxia exposure led to a FOXO-dependent increase in genes involved in cell signaling, such as kinases, GTPase regulators, and regulators of the Hippo/Yorkie pathway. Among these, we identified homeodomain-interacting protein kinase as being required for hypoxia survival. We also found that hypoxia suppresses the expression of genes involved in ribosome synthesis and egg production, and we showed that hypoxia suppresses tRNA synthesis and mRNA translation and reduces female fecundity. Among the downregulated genes, we discovered that FOXO was required for the suppression of many ribosomal protein genes and genes involved in oxidative phosphorylation, pointing to a role for FOXO in limiting energetically costly processes such as protein synthesis and mitochondrial activity upon hypoxic stress. This work uncovers a widespread role for FOXO in mediating hypoxia changes in gene expression.
The Vinca minor genome highlights conserved evolutionary traits in monoterpene indole alkaloid synthesis
Authors: Stander Emily Amor , Cuello Clément , Birer-Williams Caroline , Kulagina Natalja , Jansen Hans J , Carqueijeiro Ines , Méteignier Louis-Valentin , Vergès Valentin , Oudin Audrey , Papon Nicolas , Dirks Ron P , Jensen Michael Krogh , O’Connor Sarah Ellen , Dugé de Bernonville Thomas , Besseau Sébastien , Courdavault Vincent 
Published: October 2022

Abstract
Vinca minor, also known as the lesser periwinkle, is a well-known species from the Apocynaceae, native to central and southern Europe. This plant synthesizes monoterpene indole alkaloids, which are a class of specialized metabolites displaying a wide range of bioactive- and pharmacologically important properties. Within the almost 50 monoterpene indole alkaloids it produces, V. minor mainly accumulates vincamine, which is commercially used as a nootropic. Using a combination of Oxford Nanopore Technologies long read- and Illumina short-read sequencing, a 679,098 Mb V. minor genome was assembled into 296 scaffolds with an N50 scaffold length of 6 Mb, and encoding 29,624 genes. These genes were functionally annotated and used in a comparative genomic analysis to establish gene families and to investigate gene family expansion and contraction across the phylogenetic tree. Furthermore, homology-based monoterpene indole alkaloid gene predictions together with a metabolic analysis across 4 different V. minor tissue types guided the identification of candidate monoterpene indole alkaloid genes. These candidates were finally used to identify monoterpene indole alkaloid gene clusters, which combined with synteny analysis allowed for the discovery of a functionally validated vincadifformine-16-hydroxylase, reinforcing the potential of this dataset for monoterpene indole alkaloids gene discovery. It is expected that access to these resources will facilitate the elucidation of unknown monoterpene indole alkaloid biosynthetic routes with the potential of transferring these pathways to heterologous expression systems for large-scale monoterpene indole alkaloid production.
Clonality, inbreeding, and hybridization in two extremotolerant black yeasts
Authors: Gostinčar Cene , Sun Xiaohuan , Černoša Anja , Fang Chao , Gunde-Cimerman Nina , Song Zewei 
Published: October 2022

Abstract

Background
The great diversity of lifestyles and survival strategies observed in fungi is reflected in the many ways in which they reproduce and recombine. Although a complete absence of recombination is rare, it has been reported for some species, among them 2 extremotolerant black yeasts from Dothideomycetes: Hortaea werneckii and Aureobasidium melanogenum. Therefore, the presence of diploid strains in these species cannot be explained as the product of conventional sexual reproduction.

Results
Genome sequencing revealed that the ratio of diploid to haploid strains in both H. werneckii and A. melanogenum is about 2:1. Linkage disequilibrium between pairs of polymorphic loci and a high degree of concordance between the phylogenies of different genomic regions confirmed that both species are clonal. Heterozygosity of diploid strains is high, with several hybridizing genome pairs reaching the intergenomic distances typically seen between different fungal species. The origin of diploid strains collected worldwide can be traced to a handful of hybridization events that produced diploids, which were stable over long periods of time and distributed over large geographic areas.

Conclusions
Our results, based on the genomes of over 100 strains of 2 black yeasts, show that although they are clonal, they occasionally form stable and highly heterozygous diploid intraspecific hybrids. The mechanism of these apparently rare hybridization events, which are not followed by meiosis or haploidization, remains unknown. Both extremotolerant yeasts, H. werneckii and even more so A. melanogenum, a close relative of the intensely recombining and biotechnologically relevant Aureobasidium pullulans, provide an attractive model for studying the role of clonality and ploidy in extremotolerant fungi.
Towards fast machine-learning-assisted Bayesian posterior inference of microseismic event location and source mechanism
Authors: Piras D , Spurio Mancini A , Ferreira A M G , Joachimi B , Hobson M P 
Published: October 2022

SUMMARY
Bayesian inference applied to microseismic activity monitoring allows the accurate location of microseismic events from recorded seismograms and the estimation of the associated uncertainties. However, the forward modelling of these microseismic events, which is necessary to perform Bayesian source inversion, can be prohibitively expensive in terms of computational resources. A viable solution is to train a surrogate model based on machine learning techniques to emulate the forward model and thus accelerate Bayesian inference. In this paper, we substantially enhance previous work, which considered only sources with isotropic moment tensors. We train a machine learning algorithm on the power spectrum of the recorded pressure wave and show that the trained emulator allows complete and fast event locations for any source mechanism. Moreover, we show that our approach is computationally inexpensive, as it can be run in less than 1 hr on a commercial laptop, while yielding accurate results using less than 104 training seismograms. We additionally demonstrate how the trained emulators can be used to identify the source mechanism through the estimation of the Bayesian evidence. Finally, we demonstrate that our approach is robust to real noise as measured in field data. This work lays the foundations for efficient, accurate future joint determinations of event location and moment tensor, and associated uncertainties, which are ultimately key for accurately characterizing human-induced and natural earthquakes, and for enhanced quantitative seismic hazard assessments.
Large-scale earthquake sequence simulations on 3-D non-planar faults using the boundary element method accelerated by lattice H-matrices
Authors: Ozawa So , Ida Akihiro , Hoshino Tetsuya , Ando Ryosuke 
Published: October 2022

SUMMARY
Large-scale earthquake sequence simulations using the boundary element method (BEM) incur extreme computational costs through multiplying a dense matrix with a slip rate vector. Hierarchical matrices (H-matrices) have often been used to accelerate this multiplication. However, the complexity of the structures of the H-matrices and the communication costs between processors limit their scalability, and they therefore cannot be used efficiently in distributed memory computer systems. Lattice H-matrices have recently been proposed as a tool to improve the parallel scalability of H-matrices. In this study, we developed a method for earthquake sequence simulations applicable to 3-D non-planar faults with lattice H-matrices. We present a simulation example and verify the mesh convergence of our method for a 3-D non-planar thrust fault using rectangular and triangular discretizations. We also performed performance and scalability analyses of our code. Our simulations, using over ${10}^5$ degrees of freedom, demonstrated a parallel acceleration beyond ${10}^4$ MPI processors and a &gt; 10-fold acceleration over the best performance when the normal H-matrices are used. Using this code, we can perform unprecedented large-scale earthquake sequence simulations on geometrically complex faults with supercomputers. The software is made an open-source and freely available.
Imaging with seismic noise: improving extraction of body wave phases from the deep Earth through selective stacking based on H/V ratios
Authors: Pedersen Helle A , Mattern Flavien , Poli Piero , Stehly Laurent 
Published: October 2022

SUMMARY
Generating high-resolution images of the deep Earth remains a challenge. Body waves extracted from noise correlations hold high promise to complement earthquake-based studies, but data processing and interpretation are still under development. We develop a methodology to improve signal-to-noise ratio (SNR) of P410P and P660P, waves reflected at the top and bottom of the mantle transition zone, using data from the greater Alpine area and focussing on the second microseismic peak (2.5–10 s period). Rather than stacking all available data, we only stack correlations for days with a low ratio of amplitudes between the horizontal plane and vertical direction (H/V). Due to an improved SNR we can stack over fewer correlation pairs, with the result that horizontal resolution is significantly improved. We propose a systematic approach to determine at each study point the optimal combination of station pairs and the H/V threshold. We observe that the optimal choice of parameters is location dependent and that it is generally different for P410P and P660P. Additionally, we show that in our study area the maximum interstation distance needs to be reduced to ∼150 km for P410P to avoid that this arrival is contaminated by surface waves. Applied to the greater Alpine area we demonstrate a significant improvement of signal extraction: while P410P and P660P were only sporadically identified in standard stacks, with the new processing scheme these arrivals are clearly identified with coherent phases across large distances. We also show that amplitudes of P660P decrease drastically around longitude ∼11°E to ∼12°E, indicating that the lower discontinuity of the transition zone in that area is too broad to have a significant reflexion coefficient for P waves in the second microseismic peak.
Vanishing Treaty Claims: Investors Trapped in a Temporal Twilight Zone
Authors: Ren Raphael 
Published: October 2022

Abstract
The recent surge of arbitral awards forging new paths in the less-explored frontier of jurisdiction ratione temporis is laudable. Yet, if left unchecked, the trajectory of jurisdictional barriers expanding in depth and difficulty threatens to shrink the road of arbitration to the eye of a needle. Two emerging rules are especially worrisome: first, the right to claim under BITs vests exclusively with the investor holding the investment at the date of breach; second, the right is extinguished upon disposal of the investment. Concomitantly, once a pre-existing foreign investment is impaired by State measures, a temporal twilight zone is formed between the date of breach and date of institution of arbitration. The right to claim risks vanishing into a legal black hole along with the investment. Impecunious investors are left with a binary choice: litigate or mitigate. Ultimately, the broader lesson is for investment tribunals to avoid two common missteps when examining temporal objections: overreach of jurisdiction ratione temporis into areas more appropriately covered by the other jurisdictional dimensions (ratione materiae and ratione personae) and doctrine of abuse of process; and overreliance on principles transposed from private commercial arbitration (succession and separability).