bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diffusive-like redistribution in state-changing collisions between Rydberg atoms and ground state atoms
Authors: Geppert Philipp , Althön Max , Fichtner Daniel , Ott Herwig 
Published: June 2021

AbstractExploring the dynamics of inelastic and reactive collisions on the quantum level is a fundamental goal in quantum chemistry. Such collisions are of particular importance in connection with Rydberg atoms in dense environments since they may considerably influence both the lifetime and the quantum state of the scattered Rydberg atoms. Here, we report on the study of state-changing collisions between Rydberg atoms and ground state atoms. We employ high-resolution momentum spectroscopy to identify the final states. In contrast to previous studies, we find that the outcome of such collisions is not limited to a single hydrogenic manifold. We observe a redistribution of population over a wide range of final states. We also find that even the decay to states with the same angular momentum quantum number as the initial state, but different principal quantum number is possible. We model the underlying physical process in the framework of a short-lived Rydberg quasi-molecular complex, where a charge exchange process gives rise to an oscillating electric field that causes transitions within the Rydberg manifold. The distribution of final states shows a diffusive-like behavior.
Analysis of gene network bifurcation during optic cup morphogenesis in zebrafish
Authors: Buono Lorena , Corbacho Jorge , Naranjo Silvia , Almuedo-Castillo María , Moreno-Marmol Tania , de la Cerda Berta , Sanabria-Reinoso Estefanía , Polvillo Rocío , Díaz-Corrales Francisco-Javier , Bogdanovic Ozren , Bovolenta Paola , Martínez-Morales Juan-Ramón 
Published: June 2021

AbstractSight depends on the tight cooperation between photoreceptors and pigmented cells, which derive from common progenitors through the bifurcation of a single gene regulatory network into the neural retina (NR) and retinal-pigmented epithelium (RPE) programs. Although genetic studies have identified upstream nodes controlling these networks, their regulatory logic remains poorly investigated. Here, we characterize transcriptome dynamics and chromatin accessibility in segregating NR/RPE populations in zebrafish. We analyze cis-regulatory modules and enriched transcription factor motives to show extensive network redundancy and context-dependent activity. We identify downstream targets, highlighting an early recruitment of desmosomal genes in the flattening RPE and revealing Tead factors as upstream regulators. We investigate the RPE specification network dynamics to uncover an unexpected sequence of transcription factors recruitment, which is conserved in humans. This systematic interrogation of the NR/RPE bifurcation should improve both genetic counseling for eye disorders and hiPSCs-to-RPE differentiation protocols for cell-replacement therapies in degenerative diseases.
Nucleation of protein mesocrystals via oriented attachment
Authors: Van Driessche Alexander E. S. , Van Gerven Nani , Joosten Rick R. M. , Ling Wai Li , Bacia Maria , Sommerdijk Nico , Sleutel Mike 
Published: June 2021

AbstractSelf-assembly of proteins holds great promise for the bottom-up design and production of synthetic biomaterials. In conventional approaches, designer proteins are pre-programmed with specific recognition sites that drive the association process towards a desired organized state. Although proven effective, this approach poses restrictions on the complexity and material properties of the end-state. An alternative, hierarchical approach that has found wide adoption for inorganic systems, relies on the production of crystalline nanoparticles that become the building blocks of a next-level assembly process driven by oriented attachment (OA). As it stands, OA has not yet been observed for protein systems. Here we employ cryo-transmission electron microscopy (cryoEM) in the high nucleation rate limit of protein crystals and map the self-assembly route at molecular resolution. We observe the initial formation of facetted nanocrystals that merge lattices by means of OA alignment well before contact is made, satisfying non-trivial symmetry rules in the process. As these nanocrystalline assemblies grow larger we witness imperfect docking events leading to oriented aggregation into mesocrystalline assemblies. These observations highlight the underappreciated role of the interaction between crystalline nuclei, and the impact of OA on the crystallization process of proteins.
Fluorescence umpolung enables light-up sensing of N-acetyltransferases and nerve agents
Authors: Yan Chenxu , Guo Zhiqian , Chi Weijie , Fu Wei , Abedi Syed Ali Abbas , Liu Xiaogang , Tian He , Zhu Wei-Hong 
Published: June 2021

AbstractIntramolecular charge transfer (ICT) is a fundamental mechanism that enables the development of numerous fluorophores and probes for bioimaging and sensing. However, the electron-withdrawing targets (EWTs)-induced fluorescence quenching is a long-standing and unsolved issue in ICT fluorophores, and significantly limits the widespread applicability. Here we report a simple and generalizable structural-modification for completely overturning the intramolecular rotation driving energy, and thus fully reversing the ICT fluorophores’ quenching mode into light-up mode. Specifically, the insertion of an indazole unit into ICT scaffold can fully amplify the intramolecular rotation in donor-indazole-π-acceptor fluorophores (fluorescence OFF), whereas efficiently suppressing the rotation in their EWT-substituted system (fluorescence ON). This molecular strategy is generalizable, yielding a palette of chromophores with fluorescence umpolung that spans visible and near-infrared range. This strategy expands the bio-analytical toolboxes and allows exploiting ICT fluorophores for light-up sensing of EWTs including N-acetyltransferases and nerve agents.
The structure of ORC–Cdc6 on an origin DNA reveals the mechanism of ORC activation by the replication initiator Cdc6
Authors: Feng Xiang , Noguchi Yasunori , Barbon Marta , Stillman Bruce , Speck Christian , Li Huilin 
Published: June 2021

AbstractThe Origin Recognition Complex (ORC) binds to sites in chromosomes to specify the location of origins of DNA replication. The S. cerevisiae ORC binds to specific DNA sequences throughout the cell cycle but becomes active only when it binds to the replication initiator Cdc6. It has been unclear at the molecular level how Cdc6 activates ORC, converting it to an active recruiter of the Mcm2-7 hexamer, the core of the replicative helicase. Here we report the cryo-EM structure at 3.3 Å resolution of the yeast ORC–Cdc6 bound to an 85-bp ARS1 origin DNA. The structure reveals that Cdc6 contributes to origin DNA recognition via its winged helix domain (WHD) and its initiator-specific motif. Cdc6 binding rearranges a short α-helix in the Orc1 AAA+ domain and the Orc2 WHD, leading to the activation of the Cdc6 ATPase and the formation of the three sites for the recruitment of Mcm2-7, none of which are present in ORC alone. The results illuminate the molecular mechanism of a critical biochemical step in the licensing of eukaryotic replication origins.
Emergence and spread of a SARS-CoV-2 lineage A variant (A.23.1) with altered spike protein in Uganda
Authors: Bugembe Daniel Lule , Phan My V. T. , Ssewanyana Isaac , Semanda Patrick , Nansumba Hellen , Dhaala Beatrice , Nabadda Susan , O’Toole Áine Niamh , Rambaut Andrew , Kaleebu Pontiano , Cotten Matthew 
Published: June 2021

AbstractHere, we report SARS-CoV-2 genomic surveillance from March 2020 until January 2021 in Uganda, a landlocked East African country with a population of approximately 40 million people. We report 322 full SARS-CoV-2 genomes from 39,424 reported SARS-CoV-2 infections, thus representing 0.8% of the reported cases. Phylogenetic analyses of these sequences revealed the emergence of lineage A.23.1 from lineage A.23. Lineage A.23.1 represented 88% of the genomes observed in December 2020, then 100% of the genomes observed in January 2021. The A.23.1 lineage was also reported in 26 other countries. Although the precise changes in A.23.1 differ from those reported in the first three SARS-CoV-2 variants of concern (VOCs), the A.23.1 spike-protein-coding region has changes similar to VOCs including a change at position 613, a change in the furin cleavage site that extends the basic amino acid motif and multiple changes in the immunogenic N-terminal domain. In addition, the A.23.1 lineage has changes in non-spike proteins including nsp6, ORF8 and ORF9 that are also altered in other VOCs. The clinical impact of the A.23.1 variant is not yet clear and it has not been designated as a VOC. However, our findings of emergence and spread of this variant indicate that careful monitoring of this variant, together with assessment of the consequences of the spike protein changes for COVID-19 vaccine performance, are advisable.
Mechanism of disease and therapeutic rescue of Dok7 congenital myasthenia
Authors: Oury Julien , Zhang Wei , Leloup Nadia , Koide Akiko , Corrado Alexis D. , Ketavarapu Gayatri , Hattori Takamitsu , Koide Shohei , Burden Steven J. 
Published: June 2021

AbstractCongenital myasthenia (CM) is a devastating neuromuscular disease, and mutations in DOK7, an adaptor protein that is crucial for forming and maintaining neuromuscular synapses, are a major cause of CM1,2. The most common disease-causing mutation (DOK71124_1127 dup) truncates DOK7 and leads to the loss of two tyrosine residues that are phosphorylated and recruit CRK proteins, which are important for anchoring acetylcholine receptors at synapses. Here we describe a mouse model of this common form of CM (Dok7CM mice) and a mouse with point mutations in the two tyrosine residues (Dok72YF). We show that Dok7CM mice had severe deficits in neuromuscular synapse formation that caused neonatal lethality. Unexpectedly, these deficits were due to a severe deficiency in phosphorylation and activation of muscle-specific kinase (MUSK) rather than a deficiency in DOK7 tyrosine phosphorylation. We developed agonist antibodies against MUSK and show that these antibodies restored neuromuscular synapse formation and prevented neonatal lethality and late-onset disease in Dok7CM mice. These findings identify an unexpected cause for disease and a potential therapy for both DOK7 CM and other forms of CM caused by mutations in AGRIN, LRP4 or MUSK, and illustrate the potential of targeted therapy to rescue congenital lethality.
Differences in molecular phenotype in mouse and human hypertrophic cardiomyopathy
Authors: Vakrou Styliani , Liu Yamin , Zhu Li , Greenland Gabriela V. , Simsek Bahadir , Hebl Virginia B. , Guan Yufan , Woldemichael Kirubel , Talbot Conover C. , Aon Miguel A. , Fukunaga Ryuya , Abraham M. Roselle 
Published: June 2021

AbstractHypertrophic cardiomyopathy (HCM) is characterized by phenotypic heterogeneity. We investigated the molecular basis of the cardiac phenotype in two mouse models at established disease stage (mouse-HCM), and human myectomy tissue (human-HCM). We analyzed the transcriptome in 2 mouse models with non-obstructive HCM (R403Q-MyHC, R92W-TnT)/littermate-control hearts at 24 weeks of age, and in myectomy tissue of patients with obstructive HCM/control hearts (GSE36961, GSE36946). Additionally, we examined myocyte redox, cardiac mitochondrial DNA copy number (mtDNA-CN), mt-respiration, mt-ROS generation/scavenging and mt-Ca2+ handling in mice. We identified distinct allele-specific gene expression in mouse-HCM, and marked differences between mouse-HCM and human-HCM. Only two genes (CASQ1, GPT1) were similarly dysregulated in both mutant mice and human-HCM. No signaling pathway or transcription factor was predicted to be similarly dysregulated (by Ingenuity Pathway Analysis) in both mutant mice and human-HCM. Losartan was a predicted therapy only in TnT-mutant mice. KEGG pathway analysis revealed enrichment for several metabolic pathways, but only pyruvate metabolism was enriched in both mutant mice and human-HCM. Both mutant mouse myocytes demonstrated evidence of an oxidized redox environment. Mitochondrial complex I RCR was lower in both mutant mice compared to controls. MyHC-mutant mice had similar mtDNA-CN and mt-Ca2+ handling, but TnT-mutant mice exhibited lower mtDNA-CN and impaired mt-Ca2+ handling, compared to littermate-controls. Molecular profiling reveals differences in gene expression, transcriptional regulation, intracellular signaling and mt-number/function in 2 mouse models at established disease stage. Further studies are needed to confirm differences in gene expression between mouse and human-HCM, and to examine whether cardiac phenotype, genotype and/or species differences underlie the divergence in molecular profiles.
Incremental and decremental cardiopulmonary exercise testing protocols produce similar maximum oxygen uptake in athletes
Authors: de Sousa Nuno Manuel Frade , Bertucci Danilo Rodrigues , de Sant’Ana Gabriel Medeiros , Padua Pedro Luiz Ribeiro Angelucci , da Rosa Diogo Mello 
Published: June 2021

AbstractThe aim of the study was to evaluate and compare the maximal oxygen uptake ($$\dot{\mathrm{V}}$$

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O2max) achieved during incremental and decremental protocols in highly trained athletes. Nineteen moderate trained runners and rowers completed, on separate days, (i) an initial incremental $$\dot{\mathrm{V}}$$

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O2max test (INC) on a treadmill, followed by a verification phase (VER); (ii) a familiarization of a decremental test (DEC); (iii) a tailored DEC; (iv) a test with decremental and incremental phases (DEC-INC); (v) and a repeated incremental test (INCF). During each test $$\dot{\mathrm{V}}$$

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O2, carbon dioxide production, ventilation, heart and breath rates and ratings of perceived exertion were measured. No differences were observed in $$\dot{\mathrm{V}}$$

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O2max between INC (61.3 ± 5.2 ml kg−1 min−1) and DEC (61.1 ± 5.1 ml kg−1 min−1; average difference of ~ 11.58 ml min−1; p = 0.831), between INC and DEC-INC (60.9 ± 5.3 ml kg−1 min−1; average difference of ~ 4.8 ml min−1; p = 0.942) or between INC and INCF (60.7 ± 4.4 ml kg−1 min−1; p = 0.394). $$\dot{\mathrm{V}}$$

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O2max during VER (59.8 ± 5.1 ml kg−1 min−1) was 1.50 ± 2.20 ml kg−1 min−1 lower (~ 2.45%; p = 0.008) compared with values measured during INC. The typical error in the test-to-test changes for evaluating $$\dot{\mathrm{V}}$$

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O2max over the five tests was 2.4 ml kg−1 min−1 (95% CI 1.4–3.4 ml kg−1 min−1). Decremental tests do not elicit higher $$\dot{\mathrm{V}}$$

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O2max than incremental tests in trained runners and rowers, suggesting that a plateau in $$\dot{\mathrm{V}}$$

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O2 during the classic incremental and verification tests represents the maximum ceiling of aerobic power.
Long-chain saturated fatty acids in breast milk are associated with the pathogenesis of atopic dermatitis via induction of inflammatory ILC3s
Authors: Kong Weng Sheng , Tsuyama Naohiro , Inoue Hiroko , Guo Yun , Mokuda Sho , Nobukiyo Asako , Nakatani Nobuhiro , Yamaide Fumiya , Nakano Taiji , Kohno Yoichi , Ikeda Kazutaka , Nakanishi Yumiko , Ohno Hiroshi , Arita Makoto , Shimojo Naoki , Kanno Masamoto 
Published: June 2021

AbstractBreastfeeding influences the immune system development in infants and may even affect various immunological responses later in life. Breast milk provides a rich source of early nutrition for infant growth and development. However, the presence of certain compounds in breast milk, related to an unhealthy lifestyle or the diet of lactating mothers, may negatively impact infants. Based on a cohort study of atopic dermatitis (AD), we find the presence of damage-associated molecular patterns (DAMPs) activity in the mother’s milk. By non-targeted metabolomic analysis, we identify the long-chain saturated fatty acids (LCSFA) as a biomarker DAMPs (+) breast milk samples. Similarly, a mouse model in which breastfed offspring are fed milk high in LCSFA show AD onset later in life. We prove that LCSFA are a type of damage-associated molecular patterns, which initiate a series of inflammatory events in the gut involving type 3 innate lymphoid cells (ILC3s). A remarkable increase in inflammatory ILC3s is observed in the gut, and the migration of these ILC3s to the skin may be potential triggers of AD. Gene expression analysis of ILC3s isolated from the gut reveal upregulation of genes that increase ILC3s and chemokines/chemokine receptors, which may play a role in ILC migration to the skin. Even in the absence of adaptive immunity,Rag1knockout mice fed a high-LCSFA milk diet develop eczema, accompanied by increased gut ILC3s. We also present that gut microbiota of AD-prone PA milk-fed mice is different from non-AD OA/ND milk-fed mice. Here, we propose that early exposure to LCSFAs in infants may affect the balance of intestinal innate immunity, inducing a highly inflammatory environment with the proliferation of ILC3s and production of interleukin-17 and interleukin-22, these factors may be potential triggers or worsening factors of AD.
Gene expression profiling of perineural invasion in head and neck cutaneous squamous cell carcinoma
Authors: Eviston Timothy J. , Minaei Elahe , Mueller Simon A. , Ahmadi Navid , Ashford Bruce , Clark Jonathan R. , West Nicholas , Zhang Ping , Gupta Ruta , Ranson Marie 
Published: June 2021

AbstractPerineural invasion (PNI) is frequently associated with aggressive clinical behaviour in head and neck cutaneous squamous cell carcinoma (HNcSCC) leading to local recurrence and treatment failure. This study evaluates the gene expression profiles of HNcSCC with PNI using a differential expression analysis approach and constructs a tailored gene panel for sensitivity and specificity analysis. 45 cases of HNcSCC were stratified into three groups (Extensive, Focal and Non PNI) based on predefined clinicopathological criteria. Here we show HNcSCC with extensive PNI demonstrates significant up- and down-regulation of 144 genes associated with extracellular matrix interactions, epithelial to mesenchymal transition, cell adhesion, cellular motility, angiogenesis, and cellular differentiation. Gene expression of focal and non PNI cohorts were indistinguishable and were combined for further analyses. There is clinicopathological correlation between gene expression analysis findings and disease behaviour and a tailored panel of 10 genes was able to identify extensive PNI with 96% sensitivity and 95% specificity.
Evaluation of the BD Phoenix CPO detect panel for prediction of Ambler class carbapenemases
Authors: Jonas Daniel , Reuter Sandra , Klassen Sarah , Weber Sabine , Buck Marion , Giani Tommaso , Rossolini Gian Maria , Grundmann Hajo 
Published: June 2021

AbstractRapid detection of carbapenemases as a cause of resistance is beneficial for infection control and antimicrobial therapy. The BD Phoenix NMIC-502 panel and CPO detect test identifies presence of carbapenemases in Enterobacterales such as Klebsiella pneumoniae and assigns them to Ambler classes. To evaluate the performance of the CPO detect panel, we employed a European collection of 1222 K. pneumoniae including carbapenem non-susceptible and susceptible clinical isolates from 26 countries, for which draft genomes were available after Illumina sequencing and the presence of carbapenemase genes had been identified by ARIBA gene calling. The CPO panel detected 488 out of 494 carbapenemase-encoding isolates as positive and six as negative. One-hundred and two isolates were tested positive for carbapenemase in the absence of any carbapenemase gene. The CPO panel identified 229 out of 230 KPC-positive isolates as carbapenemase producing and classified 62 of these as class A enzyme. Similarly, the CPO panel correctly specified 167 of 182 as class D. Regarding metallo-beta-lactamases, the CPO panel assigned 78 of 90 MBL positive isolates to class B enzymes. The sensitivity of the CPO panel in detecting carbapenemase activity was 99.5%, 97.7% and 98.3% for class A, B and D enzymes, respectively. The sensitivity in assignation to Ambler class A, B and D was 27%, 86% and 91%, respectively. An overall sensitivity of 98.8% and specificity of 86% in unclassified detection of carbapenemases was observed, with frequent false positive detection of carbapenemase producing organisms, thus rendering further confirmatory tests necessary.
Epistatic interactions of genetic loci associated with age-related macular degeneration
Authors: Kiel Christina , Nebauer Christoph A. , Strunz Tobias , Stelzl Simon , Weber Bernhard H. F. 
Published: June 2021

AbstractThe currently largest genome-wide association study (GWAS) for age-related macular degeneration (AMD) defines disease association with genome-wide significance for 52 independent common and rare genetic variants across 34 chromosomal loci. Overall, these loci contain over 7200 variants and are enriched for genes with functions indicating several shared cellular processes. Still, the precise mechanisms leading to AMD pathology are largely unknown. Here, we exploit the phenomenon of epistatic interaction to identify seemingly independent AMD-associated variants that reveal joint effects on gene expression. We focus on genetic variants associated with lipid metabolism, organization of extracellular structures, and innate immunity, specifically the complement cascade. Multiple combinations of independent variants were used to generate genetic risk scores allowing gene expression in liver to be compared between low and high-risk AMD. We identified genetic variant combinations correlating significantly with expression of 26 genes, of which 19 have not been associated with AMD before. This study defines novel targets and allows prioritizing further functional work into AMD pathobiology.
Human mobility in response to COVID-19 in France, Italy and UK
Authors: Galeazzi Alessandro , Cinelli Matteo , Bonaccorsi Giovanni , Pierri Francesco , Schmidt Ana Lucia , Scala Antonio , Pammolli Fabio , Quattrociocchi Walter 
Published: June 2021

AbstractThe COVID-19 pandemic is one of the defining events of our time. National Governments responded to the global crisis by implementing mobility restrictions to slow down the spread of the virus. To assess the impact of those policies on human mobility, we perform a massive comparative analysis on geolocalized data from 13 M Facebook users in France, Italy, and the UK. We find that lockdown generally affects national mobility efficiency and smallworldness—i.e., a substantial reduction of long-range connections in favor of local paths. The impact, however, differs among nations according to their mobility infrastructure. We find that mobility is more concentrated in France and UK and more distributed in Italy. In this paper we provide a framework to quantify the substantial impact of the mobility restrictions. We introduce a percolation model mimicking mobility network disruption and find that node persistence in the percolation process is significantly correlated with the economic and demographic characteristics of countries: areas showing higher resilience to mobility disruptions are those where Value Added per Capita and Population Density are high. Our methods and findings provide important insights to enhance preparedness for global critical events and to incorporate resilience as a relevant dimension to estimate the socio-economic consequences of mobility restriction policies.