bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adolescents and adults with Fontan circulation: insights from the PREpArE-Fontan registry
Authors: Søndergaard Lars , Aboulhosn Jamil , d’Udekem Yves , Faure Céline , Franklin Wayne J , Hager Alfred , Kim Yuli Y , Muros-Le Rouzic Erwan , Rosenberg Daniel , Schwerzmann Markus , Clift Paul 
Published: July 2021

AbstractThe Patient Registry for Adolescents and Adults with Stable Fontan Circulation aims to describe a contemporary cohort of Fontan patients who could be eligible for a clinical trial investigating macitentan, an endothelin receptor antagonist. This international, non-interventional, multicentre, cross-sectional, observational registry enrolled patients with “stable” Fontan circulation ≥10 years following extra-cardiac conduit or lateral tunnel procedure. Main exclusion criteria were NYHA functional class IV, reoperation of Fontan circulation, or signs of disease worsening. Patient characteristics at enrolment are described; available data were collected during a single registration visit. Of the 266 screened patients, 254 were included in this analysis. At enrolment, median (interquartile range) age was 24 (20;30) years, 37%/63% of patients were from the USA/Europe, 54% were male, 54%/47% had undergone extra-cardiac conduit/lateral tunnel procedures, and 95% were in NYHA functional class I or II. History of arrhythmia was more common in older patients and patients with lateral tunnel; overall prevalence was 19%. Most laboratory values were within the normal range but mean creatinine clearance was abnormally low (87.7 ml/min). Angiotensin-converting enzyme inhibitors were used by 48% of patients and their use was associated with creatinine clearance <90 ml/min (p = 0.007), as was Fontan completion at an older age (p = 0.007). 53.4% of patients had clinical characteristics that could potentially meet an endothelin receptor antagonist trial’s eligibility criteria. The PREpArE-Fontan registry describes a cohort of patients who could potentially participate in an endothelin receptor antagonist trial and identified early subtle signs of Fontan failure, even in “stable” patients.
Catch me if you can: how AML and its niche escape immunotherapy
Authors: Tettamanti Sarah , Pievani Alice , Biondi Andrea , Dotti Gianpietro , Serafini Marta 
Published: July 2021

AbstractIn spite of the remarkable progress in basic and preclinical studies of acute myeloid leukemia (AML), the five-year survival rate of AML patients remains poor, highlighting the urgent need for novel and synergistic therapies. Over the past decade, increased attention has been focused on identifying suitable immunotherapeutic strategies for AML, and in particular on targeting leukemic cells and their progenitors. However, recent studies have also underlined the important contribution of the leukemic microenvironment in facilitating tumor escape mechanisms leading to disease recurrence. Here, we describe the immunological features of the AML niche, with particular attention to the crosstalk between the AML blasts and the cellular components of the altered tumor microenvironment (TME) and the mechanisms of immune escape that hamper the therapeutic effects of the most advanced treatments. Considering the AML complexity, immunotherapy approaches may benefit from a rational combination of complementary strategies aimed at preventing escape mechanisms without increasing toxicity.
Extensive bidirectional genetic overlap between bipolar disorder and cardiovascular disease phenotypes
Authors: Rødevand Linn , Bahrami Shahram , Frei Oleksandr , Chu Yunhan , Shadrin Alexey , O’Connell Kevin S. , Smeland Olav B. , Elvsåshagen Torbjørn , Hindley Guy F. L. , Djurovic Srdjan , Dale Anders M. , Lagerberg Trine V. , Steen Nils Eiel , Andreassen Ole A. 
Published: July 2021

AbstractPatients with bipolar disorder (BIP) have a high risk of cardiovascular disease (CVD), despite considerable individual variation. The mechanisms underlying comorbid CVD in BIP remain largely unknown. We investigated polygenic overlap between BIP and CVD phenotypes, including CVD risk factors and coronary artery disease (CAD). We analyzed large genome-wide association studies of BIP (n = 51,710) and CVD phenotypes (n = 159,208–795,640), using bivariate causal mixture model (MiXeR), which estimates the total amount of shared genetic variants, and conjunctional false discovery rate (FDR), which identifies specific overlapping loci. MiXeR revealed polygenic overlap between BIP and body mass index (BMI) (82%), diastolic and systolic blood pressure (20–22%) and CAD (11%) despite insignificant genetic correlations. Using conjunctional FDR < 0.05, we identified 129 shared loci between BIP and CVD phenotypes, mainly BMI (n = 69), systolic (n = 53), and diastolic (n = 53) blood pressure, of which 22 are novel BIP loci. There was a pattern of mixed effect directions of the shared loci between BIP and CVD phenotypes. Functional analyses indicated that the shared loci are linked to brain-expressed genes and involved in neurodevelopment, lipid metabolism, chromatin assembly/disassembly and intracellular processes. Altogether, the study revealed extensive polygenic overlap between BIP and comorbid CVD, implicating shared molecular genetic mechanisms. The mixed effect directions of the shared loci suggest variation in genetic susceptibility to CVD across BIP subgroups, which may underlie the heterogeneity of CVD comorbidity in BIP patients. The findings suggest more focus on targeted lifestyle interventions and personalized pharmacological treatment to reduce CVD comorbidity in BIP.
RBM15-mediated N6-methyladenosine modification affects COVID-19 severity by regulating the expression of multitarget genes
Authors: Meng Yuting , Zhang Qiong , Wang Kaihang , Zhang Xujun , Yang Rongwei , Bi Kefan , Chen Wenbiao , Diao Hongyan 
Published: July 2021

AbstractSevere coronavirus disease 2019 (COVID-19) is characterized by symptoms of lymphopenia and multiorgan damage, but the underlying mechanisms remain unclear. To explore the function of N6-methyladenosine (m6A) modifications in COVID-19, we performed microarray analyses to comprehensively characterize the m6A epitranscriptome. The results revealed distinct global m6A profiles in severe and mild COVID-19 patients. Programmed cell death and inflammatory response were the major biological processes modulated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Further, RBM15, a major m6A methyltransferase, was significantly elevated and positively correlated with disease severity. Silencing RBM15 drastically reduced lymphocyte death in vitro. Knockdown of RBM15 remarkably suppressed the expression levels of multitarget genes related to programmed cell death and inflammatory response. This study shows that SARS-CoV-2 infection alters the m6A epitranscriptome of lymphocytes, particularly in the case of severe patients. RBM15 regulated host immune response to SARS-CoV-2 by elevating m6A modifications of multitarget genes. These findings indicate that RBM15 can serve as a target for the treatment of COVID-19.
Field-induced quantum breakdown of superconductivity in magnesium diboride
Authors: Jung Soon-Gil , Lee Jung Min , Park Tae-Ho , Le Tian , Lu Xin , Lee Chan Young , Yeo Sunmog , Choi Han-Yong , Kang Won Nam , Park Tuson 
Published: July 2021

AbstractThe quantum breakdown of superconductivity (QBS) is the reverse, comprehensive approach to the appearance of superconductivity. A quantum phase transition from superconducting to insulating states tuned by using nonthermal parameters is of fundamental importance to understanding the superconducting (SC) phase but also to practical applications of SC materials. However, the mechanism of the transition to a nonzero resistive state deep in the SC state is still under debate. Here, we report a systematic study of MgB2 bilayers with different thickness ratios for undamaged and damaged layers fabricated by low-energy iron-ion irradiation. The field-induced QBS is discovered at a critical field of 3.2 Tesla (=Hc), where the quantum percolation model best explains the scaling of the magnetoresistance near Hc. As the thickness of the undamaged layer is increased, strikingly, superconductivity is recovered from the insulating state associated with the QBS, showing that destruction of quantum phase coherence among Cooper electron pairs is the origin of the QBS.
Identifying individuals with high risk of Alzheimer’s disease using polygenic risk scores
Authors: Leonenko Ganna , Baker Emily , Stevenson-Hoare Joshua , Sierksma Annerieke , Fiers Mark , Williams Julie , de Strooper Bart , Escott-Price Valentina 
Published: July 2021

AbstractPolygenic Risk Scores (PRS) for AD offer unique possibilities for reliable identification of individuals at high and low risk of AD. However, there is little agreement in the field as to what approach should be used for genetic risk score calculations, how to model the effect of APOE, what the optimal p-value threshold (pT) for SNP selection is and how to compare scores between studies and methods. We show that the best prediction accuracy is achieved with a model with two predictors (APOE and PRS excluding APOE region) with pT<0.1 for SNP selection. Prediction accuracy in a sample across different PRS approaches is similar, but individuals’ scores and their associated ranking differ. We show that standardising PRS against the population mean, as opposed to the sample mean, makes the individuals’ scores comparable between studies. Our work highlights the best strategies for polygenic profiling when assessing individuals for AD risk.
Identification of 22 susceptibility loci associated with testicular germ cell tumors
Authors: Pluta John , Pyle Louise C. , Nead Kevin T. , Wilf Rona , Li Mingyao , Mitra Nandita , Weathers Benita , D’Andrea Kurt , Almstrup Kristian , Anson-Cartwright Lynn , Benitez Javier , Brown Christopher D. , Chanock Stephen , Chen Chu , Cortessis Victoria K. , Ferlin Alberto , Foresta Carlo , Gamulin Marija , Gietema Jourik A. , Grasso Chiara , Greene Mark H. , Grotmol Tom , Hamilton Robert J. , Haugen Trine B. , Hauser Russ , Hildebrandt Michelle A. T. , Johnson Matthew E. , Karlsson Robert , Kiemeney Lambertus A. , Lessel Davor , Lothe Ragnhild A. , Loud Jennifer T. , Loveday Chey , Martin-Gimeno Paloma , Meijer Coby , Nsengimana Jérémie , Quinn David I. , Rafnar Thorunn , Ramdas Shweta , Richiardi Lorenzo , Skotheim Rolf I. , Stefansson Kari , Turnbull Clare , Vaughn David J. , Wiklund Fredrik , Wu Xifeng , Yang Daphne , Zheng Tongzhang , Wells Andrew D. , Grant Struan F. A. , Rajpert-De Meyts Ewa , Schwartz Stephen M. , Bishop D. Timothy , McGlynn Katherine A. , Kanetsky Peter A. , Nathanson Katherine L. ,   The Testicular Cancer Consortium, Kubisch Christian 
Published: July 2021

AbstractTesticular germ cell tumors (TGCT) are the most common tumor in young white men and have a high heritability. In this study, the international Testicular Cancer Consortium assemble 10,156 and 179,683 men with and without TGCT, respectively, for a genome-wide association study. This meta-analysis identifies 22 TGCT susceptibility loci, bringing the total to 78, which account for 44% of disease heritability. Men with a polygenic risk score (PRS) in the 95th percentile have a 6.8-fold increased risk of TGCT compared to men with median scores. Among men with independent TGCT risk factors such as cryptorchidism, the PRS may guide screening decisions with the goal of reducing treatment-related complications causing long-term morbidity in survivors. These findings emphasize the interconnected nature of two known pathways that promote TGCT susceptibility: male germ cell development within its somatic niche and regulation of chromosomal division and structure, and implicate an additional biological pathway, mRNA translation.
Heterogeneity-stabilized homogeneous states in driven media
Authors: Nicolaou Zachary G. , Case Daniel J. , Wee Ernest B. van der , Driscoll Michelle M. , Motter Adilson E. 
Published: July 2021

AbstractUnderstanding the relationship between symmetry breaking, system properties, and instabilities has been a problem of longstanding scientific interest. Symmetry-breaking instabilities underlie the formation of important patterns in driven systems, but there are many instances in which such instabilities are undesirable. Using parametric resonance as a model process, here we show that a range of states that would be destabilized by symmetry-breaking instabilities can be preserved and stabilized by the introduction of suitable system asymmetry. Because symmetric states are spatially homogeneous and asymmetric systems are spatially heterogeneous, we refer to this effect as heterogeneity-stabilized homogeneity. We illustrate this effect theoretically using driven pendulum array models and demonstrate it experimentally using Faraday wave instabilities. Our results have potential implications for the mitigation of instabilities in engineered systems and the emergence of homogeneous states in natural systems with inherent heterogeneities.
Stochastic pausing at latent HIV-1 promoters generates transcriptional bursting
Authors: Tantale Katjana , Garcia-Oliver Encar , Robert Marie-Cécile , L’Hostis Adèle , Yang Yueyuxiao , Tsanov Nikolay , Topno Rachel , Gostan Thierry , Kozulic-Pirher Alja , Basu-Shrivastava Meenakshi , Mukherjee Kamalika , Slaninova Vera , Andrau Jean-Christophe , Mueller Florian , Basyuk Eugenia , Radulescu Ovidiu , Bertrand Edouard 
Published: July 2021

AbstractPromoter-proximal pausing of RNA polymerase II is a key process regulating gene expression. In latent HIV-1 cells, it prevents viral transcription and is essential for latency maintenance, while in acutely infected cells the viral factor Tat releases paused polymerase to induce viral expression. Pausing is fundamental for HIV-1, but how it contributes to bursting and stochastic viral reactivation is unclear. Here, we performed single molecule imaging of HIV-1 transcription. We developed a quantitative analysis method that manages multiple time scales from seconds to days and that rapidly fits many models of promoter dynamics. We found that RNA polymerases enter a long-lived pause at latent HIV-1 promoters (>20 minutes), thereby effectively limiting viral transcription. Surprisingly and in contrast to current models, pausing appears stochastic and not obligatory, with only a small fraction of the polymerases undergoing long-lived pausing in absence of Tat. One consequence of stochastic pausing is that HIV-1 transcription occurs in bursts in latent cells, thereby facilitating latency exit and providing a rationale for the stochasticity of viral rebounds.
Reconstruction of proto-vertebrate, proto-cyclostome and proto-gnathostome genomes provides new insights into early vertebrate evolution
Authors: Nakatani Yoichiro , Shingate Prashant , Ravi Vydianathan , Pillai Nisha E. , Prasad Aravind , McLysaght Aoife , Venkatesh Byrappa 
Published: July 2021

AbstractAncient polyploidization events have had a lasting impact on vertebrate genome structure, organization and function. Some key questions regarding the number of ancient polyploidization events and their timing in relation to the cyclostome-gnathostome divergence have remained contentious. Here we generate de novo long-read-based chromosome-scale genome assemblies for the Japanese lamprey and elephant shark. Using these and other representative genomes and developing algorithms for the probabilistic macrosynteny model, we reconstruct high-resolution proto-vertebrate, proto-cyclostome and proto-gnathostome genomes. Our reconstructions resolve key questions regarding the early evolutionary history of vertebrates. First, cyclostomes diverged from the lineage leading to gnathostomes after a shared tetraploidization (1R) but before a gnathostome-specific tetraploidization (2R). Second, the cyclostome lineage experienced an additional hexaploidization. Third, 2R in the gnathostome lineage was an allotetraploidization event, and biased gene loss from one of the subgenomes shaped the gnathostome genome by giving rise to remarkably conserved microchromosomes. Thus, our reconstructions reveal the major evolutionary events and offer new insights into the origin and evolution of vertebrate genomes.
Rational construction of genome-reduced Burkholderiales chassis facilitates efficient heterologous production of natural products from proteobacteria
Authors: Liu Jiaqi , Zhou Haibo , Yang Zhiyu , Wang Xue , Chen Hanna , Zhong Lin , Zheng Wentao , Niu Weijing , Wang Sen , Ren Xiangmei , Zhong Guannan , Wang Yan , Ding Xiaoming , Müller Rolf , Zhang Youming , Bian Xiaoying 
Published: July 2021

AbstractHeterologous expression of biosynthetic gene clusters (BGCs) avails yield improvements and mining of natural products, but it is limited by lacking of more efficient Gram-negative chassis. The proteobacterium Schlegelella brevitalea DSM 7029 exhibits potential for heterologous BGC expression, but its cells undergo early autolysis, hindering further applications. Herein, we rationally construct DC and DT series genome-reduced S. brevitalea mutants by sequential deletions of endogenous BGCs and the nonessential genomic regions, respectively. The DC5 to DC7 mutants affect growth, while the DT series mutants show improved growth characteristics with alleviated cell autolysis. The yield improvements of six proteobacterial natural products and successful identification of chitinimides from Chitinimonas koreensis via heterologous expression in DT mutants demonstrate their superiority to wild-type DSM 7029 and two commonly used Gram-negative chassis Escherichia coli and Pseudomonas putida. Our study expands the panel of Gram-negative chassis and facilitates the discovery of natural products by heterologous expression.
Proximate ferromagnetic state in the Kitaev model material α-RuCl3
Authors: Suzuki H. , Liu H. , Bertinshaw J. , Ueda K. , Kim H. , Laha S. , Weber D. , Yang Z. , Wang L. , Takahashi H. , Fürsich K. , Minola M. , Lotsch B. V. , Kim B. J. , Yavaş H. , Daghofer M. , Chaloupka J. , Khaliullin G. , Gretarsson H. , Keimer B. 
Published: July 2021

Abstractα-RuCl3 is a major candidate for the realization of the Kitaev quantum spin liquid, but its zigzag antiferromagnetic order at low temperatures indicates deviations from the Kitaev model. We have quantified the spin Hamiltonian of α-RuCl3 by a resonant inelastic x-ray scattering study at the Ru L3 absorption edge. In the paramagnetic state, the quasi-elastic intensity of magnetic excitations has a broad maximum around the zone center without any local maxima at the zigzag magnetic Bragg wavevectors. This finding implies that the zigzag order is fragile and readily destabilized by competing ferromagnetic correlations. The classical ground state of the experimentally determined Hamiltonian is actually ferromagnetic. The zigzag state is stabilized by quantum fluctuations, leaving ferromagnetism – along with the Kitaev spin liquid – as energetically proximate metastable states. The three closely competing states and their collective excitations hold the key to the theoretical understanding of the unusual properties of α-RuCl3 in magnetic fields.
Observing non-ergodicity due to kinetic constraints in tilted Fermi-Hubbard chains
Authors: Scherg Sebastian , Kohlert Thomas , Sala Pablo , Pollmann Frank , Hebbe Madhusudhana Bharath , Bloch Immanuel , Aidelsburger Monika 
Published: July 2021

AbstractThe thermalization of isolated quantum many-body systems is deeply related to fundamental questions of quantum information theory. While integrable or many-body localized systems display non-ergodic behavior due to extensively many conserved quantities, recent theoretical studies have identified a rich variety of more exotic phenomena in between these two extreme limits. The tilted one-dimensional Fermi-Hubbard model, which is readily accessible in experiments with ultracold atoms, emerged as an intriguing playground to study non-ergodic behavior in a clean disorder-free system. While non-ergodic behavior was established theoretically in certain limiting cases, there is no complete understanding of the complex thermalization properties of this model. In this work, we experimentally study the relaxation of an initial charge-density wave and find a remarkably long-lived initial-state memory over a wide range of parameters. Our observations are well reproduced by numerical simulations of a clean system. Using analytical calculations we further provide a detailed microscopic understanding of this behavior, which can be attributed to emergent kinetic constraints.
KRAP tethers IP3 receptors to actin and licenses them to evoke cytosolic Ca2+ signals
Authors: Thillaiappan Nagendra Babu , Smith Holly A. , Atakpa-Adaji Peace , Taylor Colin W. 
Published: July 2021

AbstractRegulation of IP3receptors (IP3Rs) by IP3and Ca2+allows regenerative Ca2+signals, the smallest being Ca2+puffs, which arise from coordinated openings of a few clustered IP3Rs. Cells express thousands of mostly mobile IP3Rs, yet Ca2+puffs occur at a few immobile IP3R clusters. By imaging cells with endogenous IP3Rs tagged with EGFP, we show that KRas-induced actin-interacting protein (KRAP) tethers IP3Rs to actin beneath the plasma membrane. Loss of KRAP abolishes Ca2+puffs and the global increases in cytosolic Ca2+concentration evoked by more intense stimulation. Over-expressing KRAP immobilizes additional IP3R clusters and results in more Ca2+puffs and larger global Ca2+signals. Endogenous KRAP determines which IP3Rs will respond: it tethers IP3R clusters to actin alongside sites where store-operated Ca2+entry occurs, licenses IP3Rs to evoke Ca2+puffs and global cytosolic Ca2+signals, implicates the actin cytoskeleton in IP3R regulation and may allow local activation of Ca2+entry.
Development of a quantitative prediction algorithm for target organ-specific similarity of human pluripotent stem cell-derived organoids and cells
Authors: Lee Mi-Ok , Lee Su-gi , Jung Cho-Rok , Son Ye Seul , Ryu Jae-Woon , Jung Kwang Bo , Ahn Jun-Ho , Oh Jung-Hwa , Lee Hyang-Ae , Lim Jung Hwa , Kim Janghwan , Jang Insu , Choi Jinhyuk , Jung Jaeeun , Park Kunhyang , Lee Byungwook , Kim Dae-Soo , Son Mi-Young , Cho Hyun-Soo 
Published: July 2021

AbstractHuman pluripotent stem cell (hPSC)-derived organoids and cells have similar characteristics to human organs and tissues. Thus, in vitro human organoids and cells serve as a superior alternative to conventional cell lines and animal models in drug development and regenerative medicine. For a simple and reproducible analysis of the quality of organoids and cells to compensate for the shortcomings of existing experimental validation studies, a quantitative evaluation method should be developed. Here, using the GTEx database, we construct a quantitative calculation system to assess similarity to the human organs. To evaluate our system, we generate hPSC-derived organoids and cells, and detected organ similarity. To facilitate the access of our system by researchers, we develop a web-based user interface presenting similarity to the appropriate organs as percentages. Thus, this program could provide valuable information for the generation of high-quality organoids and cells and a strategy to guide proper lineage-oriented differentiation.