bluuebunny/crossref_metadata_2025 huggingface dataset:
Emerging Powers and the World Trading System
Authors: Shaffer Gregory
Published: July 2021

Victorious after World War II and the Cold War, the United States and its allies largely wrote the rules for international trade and investment. Yet, by 2020, it was the United States that became the great disrupter – disenchanted with the rules' constraints. Paradoxically, China, India, Brazil, and other emerging economies became stakeholders in and, at times, defenders of economic globalization and the rules regulating it. Emerging Powers and the World Trading System explains how this came to be and addresses the micropolitics of trade law – what has been developing under the surface of the business of trade through the practice of law, which has broad macro implications. This book provides a necessary complement to political and economic accounts for understanding why, at a time of hegemonic transition where economic security and geopolitics assume greater roles, the United States challenged, and emerging powers became defenders, of the legal order that the United States created.
IN-SAMPLE ASYMPTOTICS AND ACROSS-SAMPLE EFFICIENCY GAINS FOR HIGH FREQUENCY DATA STATISTICS
Authors: Ghysels Eric , Mykland Per , Renault Eric
Published: July 2021

We revisit in-sample asymptotic analysis extensively used in the realized volatility literature. We show that there are gains to be made in estimating current realized volatility from considering realizations in prior periods. The weighting schemes also relate to Kalman-Bucy filters, although our approach is non-Gaussian and model-free. We derive theoretical results for a broad class of processes pertaining to volatility, higher moments, and leverage. The paper also contains a Monte Carlo simulation study showing the benefits of across-sample combinations.
The Scott model of PCF in univalent type theory
Authors: de Jong Tom
Published: July 2021

We develop the Scott model of the programming language PCF in univalent type theory. Moreover, we work constructively and predicatively. To account for the non-termination in PCF, we use the lifting monad (also known as the partial map classifier monad) from topos theory, which has been extended to univalent type theory by Escardó and Knapp. Our results show that lifting is a viable approach to partiality in univalent type theory. Moreover, we show that the Scott model can be constructed in a predicative and constructive setting. Other approaches to partiality either require some form of choice or quotient inductive-inductive types. We show that one can do without these extensions.
Intranasal dexmedetomidine: the ideal drug for sedation in the pediatric echo lab?
Authors: Saudek David E , Walbergh Deborah , Bartz Peter , Shreve Sara , Schaal Amy , Lavoie Julie , Frommelt Peter C
Published: July 2021

Background:

Intranasal dexmedetomidine is an attractive option for procedural sedation in pediatrics due to ease of administration and its relatively short half-life. This study sought to compare the safety and efficacy of intranasal dexmedetomidine to a historical cohort of pediatric patients sedated using chloral hydrate in a pediatric echo lab.

Methods:

Chart review was performed to compare patients sedated between September, 2017 and October, 2019 using chloral hydrate and intranasal dexmedetomidine. Vital signs, time to sedation, duration of sedation, need for second dose of medication, rate of failed sedation, and impact on vital signs were compared between groups. Subgroup analysis was performed for those with complex and cyanotic heart disease.

Results:

Chloral hydrate was used in 356 patients and intranasal dexmedetomidine in 376. Patient age, complexity of heart disease, and duration of sedation were similar. Rates of failed sedation were very low and similar. Average heart rate and minimum heart rate were lower for those receiving intranasal dexmedetomidine than chloral hydrate. Impact on vital signs was similar for those with complex and cyanotic heart disease. No adverse events occurred in either group.

Conclusions:

Sedation with intranasal dexmedetomidine is comparable to chloral hydrate in regards to safety and efficacy for children requiring echocardiography. Consistent with the mechanism of action, patients receiving intranasal dexmedetomidine have a lower heart rate without morbidity.
Neurocognitive functioning in young adults with congenital heart disease: insights from a case-control study
Authors: Schlosser Ladina , Kessler Nora , Feldmann Maria , Wehrle Flavia , Rometsch Sarah , Greutmann Matthias , Oxenius Angela , Brugger Peter , Latal Beatrice
Published: July 2021

Background:

While there is evidence that cognitive impairment of children with congenital heart disease (CHD) may persist into adolescence, little is known about the spectrum of neurocognitive functioning of young adults with this disorder. The aim of this study was to assess neurocognitive functioning in a population of young adults with different types of CHD.

Methods:

Cross-sectional cohort study in young adults with CHD and a group-matched healthy control group. We assessed neurocognitive and general intellectual functioning with a comprehensive battery of standardised neuropsychological tests. In addition to task-based assessments, questionnaire data of executive dysfunctions in everyday life were measured with the Behaviour Rating Inventory of Executive Function – Adult Version.

Results:

A total of 67 patients (55% men) with CHD and 55 healthy controls (51% men) were included for analysis. Mean age at assessment was 26.9 (3.68) and 26.0 (3.32) years, respectively. The CHD group performed poorer in the domains of Executive Functions, Memory, Attention & Speed, and general intellectual functioning. Patients with a CHD of severe complexity were more affected than patients with simple or moderate complexity. Behaviour Rating Inventory of Executive Function – Adult Version scores indicated that patients’ self-rated deficits in behaviour regulation in everyday life was higher compared with healthy controls.

Conclusion:

Our findings indicate lower neurocognitive functioning in young adults with a CHD, particularly in those with severe defect complexity. In view of the potentially enhanced risk for cerebrovascular and neurodegenerative disease in this patient group as reported in the literature, systematic longitudinal monitoring of cognitive functioning is recommended.
Long-term results of percutaneous transluminal coronary balloon angioplasty in Kawasaki disease
Authors: Tsuda Etsuko , Takamuro Motoki , Yamamoto Kazuhiro
Published: July 2021

We report the long-term results of percutaneous transluminal coronary balloon angioplasty for early appearing localised stenosis of the left anterior descending artery caused by Kawasaki disease in two 2-year-olds. One patient had 50% restenosis and newly appearing aneurysm at 21-year-old, and the other had no restenosis at 16-year-old. They had no symptoms or cardiac events for 20 years. It is useful in the early localised stenosis without aneurysm.
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

The 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

In 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

Patients 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

Severe 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

The 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

Polygenic 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

Testicular 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

Understanding 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

Promoter-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

Ancient 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

Heterologous 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

α-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

The 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

Regulation 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

Human 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.
Nitrate-functionalized patch confers cardioprotection and improves heart repair after myocardial infarction via local nitric oxide delivery
Authors: Zhu Dashuai , Hou Jingli , Qian Meng , Jin Dawei , Hao Tian , Pan Yanjun , Wang He , Wu Shuting , Liu Shuo , Wang Fei , Wu Lanping , Zhong Yumin , Yang Zhilu , Che Yongzhe , Shen Jie , Kong Deling , Yin Meng , Zhao Qiang
Published: July 2021

Nitric oxide (NO) is a short-lived signaling molecule that plays a pivotal role in cardiovascular system. Organic nitrates represent a class of NO-donating drugs for treating coronary artery diseases, acting through the vasodilation of systemic vasculature that often leads to adverse effects. Herein, we design a nitrate-functionalized patch, wherein the nitrate pharmacological functional groups are covalently bound to biodegradable polymers, thus transforming small-molecule drugs into therapeutic biomaterials. When implanted onto the myocardium, the patch releases NO locally through a stepwise biotransformation, and NO generation is remarkably enhanced in infarcted myocardium because of the ischemic microenvironment, which gives rise to mitochondrial-targeted cardioprotection as well as enhanced cardiac repair. The therapeutic efficacy is further confirmed in a clinically relevant porcine model of myocardial infarction. All these results support the translational potential of this functional patch for treating ischemic heart disease by therapeutic mechanisms different from conventional organic nitrate drugs.
A connexin/ifi30 pathway bridges HSCs with their niche to dampen oxidative stress
Authors: Cacialli Pietro , Mahony Christopher B. , Petzold Tim , Bordignon Patrizia , Rougemont Anne-Laure , Bertrand Julien Y.
Published: July 2021

Reactive oxygen species (ROS) represent a by-product of metabolism and their excess is toxic for hematopoietic stem and progenitor cells (HSPCs). During embryogenesis, a small number of HSPCs are produced from the hemogenic endothelium, before they colonize a transient organ where they expand, for example the fetal liver in mammals. In this study, we use zebrafish to understand the molecular mechanisms that are important in the caudal hematopoietic tissue (equivalent to the mammalian fetal liver) to promote HSPC expansion. High levels of ROS are deleterious for HSPCs in this niche, however this is rescued by addition of antioxidants. We show that Cx41.8 is important to lower ROS levels in HSPCs. We also demonstrate a new role for ifi30, known to be involved in the immune response. In the hematopoietic niche, Ifi30 can recycle oxidized glutathione to allow HSPCs to dampen their levels of ROS, a role that could be conserved in human fetal liver.
Computational engineering of the oxygen electrode-electrolyte interface in solid oxide fuel cells
Authors: Cheng Kaiming , Xu Huixia , Zhang Lijun , Zhou Jixue , Wang Xitao , Du Yong , Chen Ming
Published: July 2021

The Ce0.8Gd0.2O2−δ (CGO) interlayer is commonly applied in solid oxide fuel cells (SOFCs) to prevent chemical reactions between the (La1−xSrx)(Co1−yFey)O3−δ (LSCF) oxygen electrode and the Y2O3-stabilized ZrO2 (YSZ) electrolyte. However, formation of the YSZ–CGO solid solution with low ionic conductivity and the SrZrO3 (SZO) insulating phase still happens during cell production and long-term operation, causing poor performance and degradation. Unlike many experimental investigations exploring these phenomena, consistent and quantitative computational modeling of the microstructure evolution at the oxygen electrode–electrolyte interface is scarce. We combine thermodynamic, 1D kinetic, and 3D phase-field modeling to computationally reproduce the element redistribution, microstructure evolution, and corresponding ohmic loss of this interface. The influences of different ceramic processing techniques for the CGO interlayer, i.e., screen printing and physical laser deposition (PLD), and of different processing and long-term operating parameters are explored, representing a successful case of quantitative computational engineering of the oxygen electrode–electrolyte interface in SOFCs.
Flexible entanglement-distribution network with an AlGaAs chip for secure communications
Authors: Appas Félicien , Baboux Florent , Amanti Maria I. , Lemaítre Aristide , Boitier Fabien , Diamanti Eleni , Ducci Sara
Published: July 2021

Quantum communication networks enable applications ranging from highly secure communication to clock synchronization and distributed quantum computing. Miniaturized, flexible, and cost-efficient resources will be key elements for ensuring the scalability of such networks as they progress towards large-scale deployed infrastructures. Here, we bring these elements together by combining an on-chip, telecom-wavelength, broadband entangled photon source with industry-grade flexible-grid wavelength division multiplexing techniques, to demonstrate reconfigurable entanglement distribution between up to 8 users in a resource-optimized quantum network topology. As a benchmark application we use quantum key distribution, and show low error and high secret key generation rates across several frequency channels, over both symmetric and asymmetric metropolitan-distance optical fibered links and including finite-size effects. By adapting the bandwidth allocation to specific network constraints, we also illustrate the flexible networking capability of our configuration. Together with the potential of our semiconductor source for distributing secret keys over a 60 nm bandwidth with commercial multiplexing technology, these results offer a promising route to the deployment of scalable quantum network architectures.
Developmental brain dynamics of numerical and arithmetic abilities
Authors: Vogel Stephan E. , De Smedt Bert
Published: July 2021

The development of numerical and arithmetic abilities constitutes a crucial cornerstone in our modern and educated societies. Difficulties to acquire these central skills can lead to severe consequences for an individual’s well-being and nation’s economy. In the present review, we describe our current broad understanding of the functional and structural brain organization that supports the development of numbers and arithmetic. The existing evidence points towards a complex interaction among multiple domain-specific (e.g., representation of quantities and number symbols) and domain-general (e.g., working memory, visual–spatial abilities) cognitive processes, as well as a dynamic integration of several brain regions into functional networks that support these processes. These networks are mainly, but not exclusively, located in regions of the frontal and parietal cortex, and the functional and structural dynamics of these networks differ as a function of age and performance level. Distinctive brain activation patterns have also been shown for children with dyscalculia, a specific learning disability in the domain of mathematics. Although our knowledge about the developmental brain dynamics of number and arithmetic has greatly improved over the past years, many questions about the interaction and the causal involvement of the abovementioned functional brain networks remain. This review provides a broad and critical overview of the known developmental processes and what is yet to be discovered.
Gridded daily weather data for North America with comprehensive uncertainty quantification
Authors: Thornton Peter E. , Shrestha Rupesh , Thornton Michele , Kao Shih-Chieh , Wei Yaxing , Wilson Bruce E.
Published: July 2021

Access to daily high-resolution gridded surface weather data based on direct observations and over long time periods is essential for many studies and applications including vegetation, wildlife, soil health, hydrological modelling, and as driver data in Earth system models. We present Daymet V4, a 40-year daily meteorological dataset on a 1 km grid for North America, Hawaii, and Puerto Rico, providing temperature, precipitation, shortwave radiation, vapor pressure, snow water equivalent, and day length. The dataset includes an objective quantification of uncertainty based on strict cross-validation analysis for temperature and precipitation results. The dataset represents several improvements from a previous version, and this data descriptor provides complete documentation for updated methods. Improvements include: reductions in the timing bias of input reporting weather station measurements; improvement to the three-dimensional regression model techniques in the core algorithm; and a novel approach to handling high elevation temperature measurement biases. We show cross-validation analyses with the underlying weather station data to demonstrate the technical validity of new dataset generation methods, and to quantify improved accuracy.
Deep-learning framework and computer assisted fatty infiltration analysis for the supraspinatus muscle in MRI
Authors: Ro Kyunghan , Kim Joo Young , Park Heeseol , Cho Baek Hwan , Kim In Young , Shim Seung Bo , Choi In Young , Yoo Jae Chul
Published: July 2021

Occupation ratio and fatty infiltration are important parameters for evaluating patients with rotator cuff tears. We analyzed the occupation ratio using a deep-learning framework and studied the fatty infiltration of the supraspinatus muscle using an automated region-based Otsu thresholding technique. To calculate the amount of fatty infiltration of the supraspinatus muscle using an automated region-based Otsu thresholding technique. The mean Dice similarity coefficient, accuracy, sensitivity, specificity, and relative area difference for the segmented lesion, measuring the similarity of clinician assessment and that of a deep neural network, were 0.97, 99.84, 96.89, 99.92, and 0.07, respectively, for the supraspinatus fossa and 0.94, 99.89, 93.34, 99.95, and 2.03, respectively, for the supraspinatus muscle. The fatty infiltration measure using the Otsu thresholding method significantly differed among the Goutallier grades (Grade 0; 0.06, Grade 1; 4.68, Grade 2; 20.10, Grade 3; 42.86, Grade 4; 55.79, p < 0.0001). The occupation ratio and fatty infiltration using Otsu thresholding demonstrated a moderate negative correlation (ρ = − 0.75, p < 0.0001). This study included 240 randomly selected patients who underwent shoulder magnetic resonance imaging (MRI) from January 2015 to December 2016. We used a fully convolutional deep-learning algorithm to quantitatively detect the fossa and muscle regions by measuring the occupation ratio of the supraspinatus muscle. Fatty infiltration was objectively evaluated using the Otsu thresholding method. The proposed convolutional neural network exhibited fast and accurate segmentation of the supraspinatus muscle and fossa from shoulder MRI, allowing automatic calculation of the occupation ratio. Quantitative evaluation using a modified Otsu thresholding method can be used to calculate the proportion of fatty infiltration in the supraspinatus muscle. We expect that this will improve the efficiency and objectivity of diagnoses by quantifying the index used for shoulder MRI.
An efficient electrochemical sensing of hazardous catechol and hydroquinone at direct green 6 decorated carbon paste electrode
Authors: Chetankumar K. , Kumara Swamy B. E. , Sharma S. C. , Hariprasad S. A.
Published: July 2021

In this proposed work, direct green 6 (DG6) decorated carbon paste electrode (CPE) was fabricated for the efficient simultaneous and individual sensing of catechol (CA) and hydroquinone (HY). Electrochemical deeds of the CA and HY were carried out by cyclic voltammetry (CV) and differential pulse voltammetry (DPV) at poly-DG6-modfied carbon paste electrode (Po-DG6-MCPE). Using scanning electron microscopy (SEM) studied the surface property of unmodified CPE (UCPE) and Po-DG6-MCPE. The decorated sensor displayed admirable electrocatalytic performance with fine stability, reproducibility, selectivity, low limit of detection (LLOD) for HY (0.11 μM) and CC (0.09 μM) and sensor process was originated to be adsorption-controlled phenomena. The Po-DG6-MCPE sensor exhibits well separated two peaks for HY and CA in CV and DPV analysis with potential difference of 0.098 V. Subsequently, the sensor was practically applied for the analysis in tap water and it consistent in-between for CA 93.25–100.16% and for HY 97.25–99.87% respectively.
Loss of αklotho causes reduced motor ability and short lifespan in zebrafish
Authors: Ogura Yurie , Kaneko Ryoji , Ujibe Kota , Wakamatsu Yuma , Hirata Hiromi
Published: July 2021

The klotho gene encodes a transmembrane protein αKlotho that interacts with a fibroblast growth factor (FGF) receptor in renal tubular epithelial cells and functions as a co-receptor for FGF23, which is an osteocytes-derived hormone. This bone-to-kidney signal promotes urinary phosphate excretion. Interestingly, αKlotho knockout mice show an accelerated aging and a shortened life span. Similarly, C. elegans lacking the αklotho homologue showed a short life span. However, the physiological basis of aging-related function of αklotho remain unclear. The αklotho-deficient vertebrate animals other than mice have been awaited as an alternative model of premature aging. We here employed zebrafish in our study and revealed that αklotho mutant zebrafish appeared to be normal at 3 months postfertilization (mpf) but eventually underwent premature death by 9 mpf, while normal zebrafish is known to survive for 42 months. We also assessed the motor ability of zebrafish in a forced swimming assay and found that αklotho mutant zebrafish displayed reduced swimming performance before their survival declined. A recent study also reported a similar finding that αklotho-deficient zebrafish exhibited a short life span and reduced spontaneous movements. Taken together, these results suggest that αKlotho mutant zebrafish show premature aging and are useful to investigate aging in vertebrates.
Decreased thalamo-cortico connectivity during an implicit sequence motor learning task and 7 days escitalopram intake
Authors: Molloy Eóin N. , Zsido Rachel G. , Piecha Fabian A. , Beinhölzl Nathalie , Scharrer Ulrike , Zheleva Gergana , Regenthal Ralf , Sehm Bernhard , Nikulin Vadim V. , Möller Harald E. , Villringer Arno , Sacher Julia , Mueller Karsten
Published: July 2021

Evidence suggests that selective serotonin reuptake inhibitors (SSRIs) reorganize neural networks via a transient window of neuroplasticity. While previous findings support an effect of SSRIs on intrinsic functional connectivity, little is known regarding the influence of SSRI-administration on connectivity during sequence motor learning. To investigate this, we administered 20 mg escitalopram or placebo for 1-week to 60 healthy female participants undergoing concurrent functional magnetic resonance imaging and sequence motor training in a double-blind randomized controlled design. We assessed task-modulated functional connectivity with a psycho-physiological interaction (PPI) analysis in the thalamus, putamen, cerebellum, dorsal premotor, primary motor, supplementary motor, and dorsolateral prefrontal cortices. Comparing an implicit sequence learning condition to a control learning condition, we observed decreased connectivity between the thalamus and bilateral motor regions after 7 days of escitalopram intake. Additionally, we observed a negative correlation between plasma escitalopram levels and PPI connectivity changes, with higher escitalopram levels being associated with greater thalamo-cortico decreases. Our results suggest that escitalopram enhances network-level processing efficiency during sequence motor learning, despite no changes in behaviour. Future studies in more diverse samples, however, with quantitative imaging of neurochemical markers of excitation and inhibition, are necessary to further assess neural responses to escitalopram.
Deep Learning Method to Accelerate Discovery of Hybrid Polymer-Graphene Composites
Authors: Shayeganfar Farzaneh , Shahsavari Rouzbeh
Published: July 2021

Interfacial encoded properties of polymer adlayers adsorbed on the graphene (GE) and silicon dioxide (SiO2) have been constituted a scaffold for the creation of new materials. The holistic understanding of nanoscale intermolecular interaction of 1D/2D polymer assemblies on substrate is the key to bottom-up design of molecular devices. We develop an integrated multidisciplinary approach based on electronic structure computation [density functional theory (DFT)] and big data mining [machine learning (ML)] in parallel with neural network (NN) and statistical analysis (SA) to design hybrid polymers from assembly on substrate. Here we demonstrate that interfacial pressure and structural deformation of polymer network adsorbed on GE and SiO2 offer unique directions for the fabrication of 1D/2D polymers using only a small number of simple molecular building blocks. Our findings serve as the platform for designing a wide range of typical inorganic heterostructures, involving noncovalent intermolecular interaction observed in many nanoscale electronic devices.