bluuebunny/crossref_metadata_2025 huggingface dataset:
Rationally repurposed nitroxoline inhibits preclinical models of Epstein–Barr virus-associated lymphoproliferation
Authors: Ibáñez de Garayo Maite , Liu Wendi , Rondeau Nicole C. , Damoci Christopher B. , Miranda JJ L.
Published: June 2021

Repurposing of currently used drugs for new indications benefits from known experience with those agents. Rational repurposing can be achieved when newly uncovered molecular activities are leveraged against diseases that utilize those mechanisms. Nitroxoline is an antibiotic with metal-chelating activity used to treat urinary tract infections. This small molecule also inhibits the function of bromodomain and extraterminal (BET) proteins that regulate oncogene expression in cancer. Lymphoproliferation driven by the Epstein–Barr virus (EBV) depends on these same proteins. We therefore tested the efficacy of nitroxoline against cell culture and small animal models of EBV-associated lymphoproliferation. Nitroxoline indeed reduces cell and tumor growth. Nitroxoline also acts faster than the prototype BET inhibitor JQ1. We suggest that this rational repurposing may hold translational promise.
India-Asia collision as a driver of atmospheric CO2 in the Cenozoic
Authors: Guo Zhengfu , Wilson Marjorie , Dingwell Donald B. , Liu Jiaqi
Published: June 2021

Deep Earth degassing is a critical forcing factor for atmospheric CO2 variations and palaeoclimate changes in Earth’s history. For the Cenozoic, the key driving mechanism of atmospheric CO2 variations remains controversial. Here we analyse three stages of collision-related magmatism in Tibet, which correspond temporally with the three major stages of atmospheric CO2 variations in the Cenozoic and explore the possibility of a causal link between these phenomena. To this end we present geochemical data for the three stages of magmatic rocks in Tibet, which we use to inform a model calculating the continental collision-induced CO2 emission flux associated with the evolving Neo-Tethyan to continental subduction over the Cenozoic. The correlation between our modelled CO2 emission rates and the global atmospheric CO2 curve is consistent with the hypothesis that the India-Asia collision was the primary driver of changes in atmospheric CO2 over the Cenozoic.
Melt volume at Atlantic volcanic rifted margins controlled by depth-dependent extension and mantle temperature
Authors: Lu Gang , Huismans Ritske S.
Published: June 2021

Breakup volcanism along rifted passive margins is highly variable in time and space. The factors controlling magmatic activity during continental rifting and breakup are not resolved and controversial. Here we use numerical models to investigate melt generation at rifted margins with contrasting rifting styles corresponding to those observed in natural systems. Our results demonstrate a surprising correlation of enhanced magmatism with margin width. This relationship is explained by depth-dependent extension, during which the lithospheric mantle ruptures earlier than the crust, and is confirmed by a semi-analytical prediction of melt volume over margin width. The results presented here show that the effect of increased mantle temperature at wide volcanic margins is likely over-estimated, and demonstrate that the large volumes of magmatism at volcanic rifted margin can be explained by depth- dependent extension and very moderate excess mantle potential temperature in the order of 50–80 °C, significantly smaller than previously suggested.
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

Exploring 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

Sight 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

Self-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

Intramolecular 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

The 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

Here, 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

Congenital 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

Hypertrophic 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

The 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

Breastfeeding 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

Perineural 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

Rapid 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

The 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

The 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.
Focused CRISPR-Cas9 genetic screening reveals USO1 as a vulnerability in B-cell acute lymphoblastic leukemia
Authors: Jaiswal Amit Kumar , Truong Hellen , Tran Tiffany M. , Lin Tasha L. , Casero David , Alberti Michael O. , Rao Dinesh S.
Published: June 2021

Post-transcriptional gene regulation, including that by RNA binding proteins (RBPs), has recently been described as an important mechanism in cancer. We had previously identified a set of RBPs that were highly dysregulated in B-cell acute lymphoblastic leukemia (B-ALL) with MLL translocations, which carry a poor prognosis. Here, we sought to functionally characterize these dysregulated RBP genes by performing a focused CRISPR dropout screen in B-ALL cell lines, finding dependencies on several genes including EIF3E, EPRS and USO1. Validating our findings, CRISPR/Cas9-mediated disruption of USO1 in MLL-translocated B-ALL cells reduced cell growth, promoted cell death, and altered the cell cycle. Transcriptomic analysis of USO1-deficient cells revealed alterations in pathways related to mTOR signaling, RNA metabolism, and targets of MYC. In addition, USO1-regulated genes from these experimental samples were significantly and concordantly correlated with USO1 expression in primary samples collected from B-ALL patients. Lastly, we found that loss of Uso1 inhibited colony formation of MLL-transformed in primary bone marrow cells from Cas9-EGFP mice. Together, our findings demonstrate an approach to performing focused sub-genomic CRISPR screens and highlight a putative RBP vulnerability in MLL-translocated B-ALL, thus identifying potential therapeutic targets in this disease.
Correlative microscopy and block-face imaging (CoMBI) method for both paraffin-embedded and frozen specimens
Authors: Ishii Nobukazu , Tajika Yuki , Murakami Tohru , Galipon Josephine , Shirahata Hiroyoshi , Mukai Ryo , Uehara Daisuke , Kaneko Ryosuke , Yamazaki Yuichi , Yoshimoto Yuhei , Iwasaki Hirohide
Published: June 2021

Correlative microscopy and block-face imaging (CoMBI), a method that we previously developed, is characterized by the ability to correlate between serial block-face images as 3-dimensional (3D) datasets and sections as 2-dimensional (2D) microscopic images. CoMBI has been performed for the morphological analyses of various biological specimens, and its use is expanding. However, the conventional CoMBI system utilizes a cryostat, which limits its compatibility to only frozen blocks and the resolution of the block-face image. We developed a new CoMBI system that can be applied to not only frozen blocks but also paraffin blocks, and it has an improved magnification for block-face imaging. The new system, called CoMBI-S, comprises sliding-type sectioning devices and imaging devices, and it conducts block slicing and block-face imaging automatically. Sections can also be collected and processed for microscopy as required. We also developed sample preparation methods for improving the qualities of the block-face images and 3D rendered volumes. We successfully obtained correlative 3D datasets and 2D microscopic images of zebrafish, mice, and fruit flies, which were paraffin-embedded or frozen. In addition, the 3D datasets at the highest magnification could depict a single neuron and bile canaliculus.
Establishment and characterization of a new human colon cancer cell line, PUMC-CRC1
Authors: Bian Xiaocui , Cao Fang , Wang Xiaowan , Hou Yuhong , Zhao Haitao , Liu Yuqin
Published: June 2021

Colorectal cancer (CRC) is one of the most common and fatal gastrointestinal cancers worldwide. Considering their diversity, the establishment of new continuous CRC cell lines with clear genetic backgrounds will provide useful tools for exploring molecular mechanisms, screening and evaluating antitumor drugs in CRC studies. Our de novo CRC cell line, PUMC-CRC1 (Peking Union Medical College Colorectal Cancer 1) was derived from a 47-year-old Chinese female patient diagnosed with moderately to poorly differentiated colon adenocarcinoma. Multiple experiments were used for full characterization. The new cell line was epithelial-like and was passaged for more than 40 times, with a population doubling time of 44 h in vitro, detected by cell counts. The cells exhibited complicated chromosomal abnormalities. The tumor formation rate in SCID mice was 100%. The xenograft tumor was adenocarcinoma with poor to moderate differentiation by Haematoxylin and Eosin staining (H&E) sections. Immunohistochemistry (IHC) analysis and next-generation sequencing (NGS) revealed microsatellite stable (MSS), APC (p.T1493fs) inactivation, KRAS (p.G12V) activation, and SMAD4 (p.V506A) mutation. Quality control of the cell line proved mycoplasma negative and identical STR profile with that of the original tissue, and no interspecific or intraspecific cross contamination was detected. In conclusion, PUMC-CRC1 was a newly established and well characterized human colon cancer cell line, which might be a good model for both in vitro and in vivo studies of the mechanism of colon cancer progression and the treatment strategies for MSS CRC.
Psychophysical profiles in super-recognizers
Authors: Nador Jeffrey D. , Zoia Matteo , Pachai Matthew V. , Ramon Meike
Published: June 2021

Facial identity matching ability varies widely, ranging from prosopagnosic individuals (who exhibit profound impairments in face cognition/processing) to so-called super-recognizers (SRs), possessing exceptional capacities. Yet, despite the often consequential nature of face matching decisions—such as identity verification in security critical settings—ability assessments tendentially rely on simple performance metrics on a handful of heterogeneously related subprocesses, or in some cases only a single measured subprocess. Unfortunately, methodologies of this ilk leave contributions of stimulus information to observed variations in ability largely un(der)specified. Moreover, they are inadequate for addressing the qualitative or quantitative nature of differences between SRs’ abilities and those of the general population. Here, therefore, we sought to investigate individual differences—among SRs identified using a novel conservative diagnostic framework, and neurotypical controls—by systematically varying retinal availability, bandwidth, and orientation of faces’ spatial frequency content in two face matching experiments. Psychophysical evaluations of these parameters’ contributions to ability reveal that SRs more consistently exploit the same spatial frequency information, rather than suggesting qualitatively different profiles between control observers and SRs. These findings stress the importance of optimizing procedures for SR identification, for example by including measures quantifying the consistency of individuals’ behavior.
Initial radiological signs of dentofacial deformity in juvenile idiopathic arthritis
Authors: Stoustrup Peter , Traberg Michelle Sys , Matzen Louise Hauge , Glerup Mia , Küseler Annelise , Herlin Troels , Pedersen Thomas Klit
Published: June 2021

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood and the temporomandibular joint (TMJ) is often involved. TMJ arthritis in growing individuals can cause deformation of facial skeleton (dentofacial deformity) and TMJ components (TMJ deformity). Treatment outcome hinges on early initiation of anti-inflammatory treatment and orthopaedic treatment with dental splints. The aim of the present study was to characterize the radiological signs of dentofacial deformity in patients with a JIA-induced need for orthopaedic treatment. We retrospectively studied 96 patients with JIA and 20 non-JIA controls to identify the initial radiological signs of JIA-induced dentofacial deformity leading to initiation of orthopaedic treatment. We found that initial radiological signs of dentofacial deformities were subtle and characterized by minor mandibular asymmetry and occlusal plane steepening. Radiological findings of TMJ deformity associated with initial dentofacial deformity were frequent and characterized by condylar articular surface flattening (OR 8.42), condylar subcortical cyst (OR 5.94), condylar surface erosion (OR 5.38) and condylar deviation in form (OR 25.39). Radiological signs of TMJ deformity were also documented in TMJs considered “healthy” during initial clinical and radiological examination. This study presents new knowledge of importance for early diagnosis of dentofacial deformity in JIA. Early diagnosis of dentofacial deformity is important as treatment outcome is greatly influenced by timely initiation.
Quantitative not qualitative histology differentiates aneurysmal from nondilated ascending aortas and reveals a net gain of medial components
Authors: Yousef Sameh , Matsumoto Nana , Dabe Issam , Mori Makoto , Landry Alden B. , Lee Shin-Rong , Kawamura Yuki , Yang Chen , Li Guangxin , Assi Roland , Vallabhajosyula Prashanth , Geirsson Arnar , Moeckel Gilbert , Humphrey Jay D. , Tellides George
Published: June 2021

Medial degeneration is a common histopathological finding in aortopathy and is considered a mechanism for dilatation. We investigated if medial degeneration is specific for sporadic thoracic aortic aneurysms versus nondilated aortas. Specimens were graded by pathologists, blinded to the clinical diagnosis, according to consensus histopathological criteria. The extent of medial degeneration by qualitative (semi-quantitative) assessment was not specific for aneurysmal compared to nondilated aortas. In contrast, blinded quantitative assessment of elastin amount and medial cell number distinguished aortic aneurysms and referent specimens, albeit with marked overlap in results. Specifically, the medial fraction of elastin decreased from dilution rather than loss of protein as cross-sectional amount was maintained while the cross-sectional number, though not density, of smooth muscle cells increased in proportion to expansion of the media. Furthermore, elastic lamellae did not thin and interlamellar distance did not diminish as expected for lumen dilatation, implying a net gain of lamellar elastin and intralamellar cells or extracellular matrix during aneurysmal wall remodeling. These findings support the concepts that: (1) medial degeneration need not induce aortic aneurysms, (2) adaptive responses to altered mechanical stresses increase medial tissue, and (3) greater turnover, not loss, of mural cells and extracellular matrix associates with aortic dilatation.
A simple high-speed random number generator with minimal post-processing using a random Raman fiber laser
Authors: Monet Frédéric , Boisvert Jean-Sébastien , Kashyap Raman
Published: June 2021

A simple novel method for random number generation is presented, based on a random Raman fiber laser. This laser is built in a half-open cavity scheme, closed on one side by a narrow-linewidth 100 mm fiber Bragg grating. The interaction between the randomly excited lasing modes of this laser, in addition to nonlinear effects such as modulation instability, allow the generation of random bits at rates of up to 540 Gbps with minimal post processing. Evaluation of the resulting bit streams’ randomness by the NIST statistical test suite highlights the importance of evaluating the physical entropy content, as bit sequences generated by this random laser pass all the statistical tests with a significance level of 0.01, despite being generated at more than twice the theoretical entropy generation speed.
Silage quality and biogas production from Spartina pectinata L. fermented with a novel xylan-degrading strain of Lactobacillus buchneri M B/00077
Authors: Kupryś-Caruk Marta , Choińska Renata , Dekowska Agnieszka , Piasecka-Jóźwiak Katarzyna
Published: June 2021

The aim of the current study was to determine the ability of the Lactobacillus buchneri M B/00077 strain to degrade xylan, its impact on the quality of silage made from the lignocellulosic biomass of Spartina pectinata L., as well as the efficiency of biogas production. In the model in vitro conditions the L. buchneri M B/00077 strain was able to grow in a medium using xylan as the sole source of carbon, and xylanolytic activity was detected in the post-culture medium. In the L. buchneri M B/00077 genome, genes encoding endo-1,4-xylanase and β-xylosidase were identified. The silages prepared using L. buchneri M B/00077 were characterized by a higher concentration of acetic and propionic acids compared to the controls or the silages prepared with the addition of commercial xylanase. The addition of bacteria increased the efficiency of biogas production. From the silages treated with L. buchneri M B/00077, 10% and 20% more biogas was obtained than from the controls and the silages treated with commercial xylanase, respectively. The results of the current study indicated the strain L. buchneri M B/00077 as being a promising candidate for further application in the field of pretreatment of lignocellulosic biomass.
Precise CAG repeat contraction in a Huntington’s Disease mouse model is enabled by gene editing with SpCas9-NG
Authors: Oura Seiya , Noda Taichi , Morimura Naoko , Hitoshi Seiji , Nishimasu Hiroshi , Nagai Yoshitaka , Nureki Osamu , Ikawa Masahito
Published: June 2021

The clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 system is a research hotspot in gene therapy. However, the widely used Streptococcus pyogenes Cas9 (WT-SpCas9) requires an NGG protospacer adjacent motif (PAM) for target recognition, thereby restricting targetable disease mutations. To address this issue, we recently reported an engineered SpCas9 nuclease variant (SpCas9-NG) recognizing NGN PAMs. Here, as a feasibility study, we report SpCas9-NG-mediated repair of the abnormally expanded CAG repeat tract in Huntington’s disease (HD). By targeting the boundary of CAG repeats with SpCas9-NG, we precisely contracted the repeat tracts in HD-mouse-derived embryonic stem (ES) cells. Further, we confirmed the recovery of phenotypic abnormalities in differentiated neurons and animals produced from repaired ES cells. Our study shows that SpCas9-NG can be a powerful tool for repairing abnormally expanded CAG repeats as well as other disease mutations that are difficult to access with WT-SpCas9.
Multiomic analysis of the Arabian camel (Camelus dromedarius) kidney reveals a role for cholesterol in water conservation
Authors: Alvira-Iraizoz Fernando , Gillard Benjamin T. , Lin Panjiao , Paterson Alex , Pauža Audrys G. , Ali Mahmoud A. , Alabsi Ammar H. , Burger Pamela A. , Hamadi Naserddine , Adem Abdu , Murphy David , Greenwood Michael P.
Published: June 2021

The Arabian camel (Camelus dromedarius) is the most important livestock animal in arid and semi-arid regions and provides basic necessities to millions of people. In the current context of climate change, there is renewed interest in the mechanisms that enable camelids to survive in arid conditions. Recent investigations described genomic signatures revealing evolutionary adaptations to desert environments. We now present a comprehensive catalogue of the transcriptomes and proteomes of the dromedary kidney and describe how gene expression is modulated as a consequence of chronic dehydration and acute rehydration. Our analyses suggested an enrichment of the cholesterol biosynthetic process and an overrepresentation of categories related to ion transport. Thus, we further validated differentially expressed genes with known roles in water conservation which are affected by changes in cholesterol levels. Our datasets suggest that suppression of cholesterol biosynthesis may facilitate water retention in the kidney by indirectly facilitating the AQP2-mediated water reabsorption.
A low-cost post-processing technique improves weather forecasts around the world
Authors: Hewson Timothy David , Pillosu Fatima Maria
Published: June 2021

Computer-generated weather forecasts divide the Earth’s surface into gridboxes, each currently spanning about 400 km2, and predict one value per gridbox. If weather varies markedly within a gridbox, forecasts for specific sites inevitably fail. Here we present a statistical post-processing method for ensemble forecasts that accounts for the degree of variation within each gridbox, bias on the gridbox scale, and the weather dependence of each. When applying this post-processing, skill improves substantially across the globe; for extreme rainfall, for example, useful forecasts extend 5 days ahead, compared to less than 1 day without post-processing. Skill improvements are attributed to creation of huge calibration datasets by aggregating, globally rather than locally, forecast-observation differences wherever and whenever the observed “weather type” was similar. A strong focus on meteorological understanding also contributes. We suggest that applications for our methodology include improved flash flood warnings, physics-related insights into model weaknesses and global pointwise re-analyses.
A nanostructured microfluidic device for plasmon-assisted electrochemical detection of hydrogen peroxide released from cancer cells
Authors: del Real Mata Carolina , Siavash Moakhar Roozbeh , Hosseini Imman I. , Jalali Mahsa , Mahshid Sara
Published: June 2021

A nanostructured microfluidic device, featuring a series of self-organized gold nanocavities, enhanced with graphene nanosheets, for ultrasensitive, quantitative, and plasmon-assisted electrochemical detection of H2O2 released from cancer cells.
Interconnection of organic–inorganic hybrid nano-building blocks towards thermally robust mesoporous structures
Authors: Tarutani Naoki , Sato Riona , Yamazaki Wataru , Katagiri Kiyofumi , Inumaru Kei , Ishigaki Takamasa
Published: June 2021

The robustness of layered metal hydroxide nanocrystal-based mesoporous materials was improved by interconnecting the nanocrystals through polymerization of intercalated organic anions.
Triple-signaling amplification strategy based electrochemical sensor design: boosting synergistic catalysis in metal–metalloporphyrin–covalent organic frameworks for sensitive bisphenol A detection
Authors: Xie Yao , Wang Na , Sun Xin , Chu Huacong , Wang Yang , Hu Xiaoya
Published: June 2021

A novel triple-signaling electrochemical sensor was constructed for bisphenol A detection using metal–metalloporphyrin–covalent organic frameworks.
Solid solutions of flexible host–guest supramolecules for tuning molecular motion and phase transitions
Authors: Zhou Xun-Hui , Zeng Ying , Tang Shao-Bin , Yu Zi-Ru , Cao Li-Ming , Du Zi-Yi , He Chun-Ting
Published: June 2021

By utilizing supramolecular complex as a deformable/elastic substitutional component, we put forward a unique strategy for the formation of molecular solid solutions, which can modulate the molecular motion and phase transition in molecular solids.
The copper-catalyzed synthesis of dihydrooxazoles from α,β-unsaturated ketoximes and activated ketones
Authors: Rong Binsen , Xu Gaochen , Yan Huan , Zhang Sai , Wu Qinghuan , Zhu Ning , Duan Jindian , Guo Kai
Published: June 2021

A copper-catalyzed [3+2]-type condensation reaction between α,β-unsaturated ketoximes and activated ketones for the synthesis of dihydrooxazoles is described.
Highlights from Faraday Discussion 228: time resolved imaging of photo-induced dynamics
Authors: Dixit Gopal , Kirrander Adam
Published: June 2021

A virtual Faraday Discussions meeting was held on the topic of ‘Time resolved imaging of photo-induced dynamics’. This report covers the highlights of this meeting, including brief summaries of the papers discussed.
Bent-bis(triazolyl)-based coordination polymers tuned by dicarboxylate ligands: syntheses, structures and properties
Authors: Tseng Tien-Wen , Luo Tzuoo-Tsair , Tseng Kuo-Yang , Hong Yu-Xian , Huang Guang-Cheng
Published: June 2021

Seven new coordination polymers based on the bent 1,1'-(oxybis(1,4-phenylene))-bis(1H-1,2,4-triazole) ligand, with diverse structures and novel topologies, that are directed by the dicarboxylate ligands.
A first-principles study of phthalocyanine-based multifunctional spintronic molecular devices
Authors: Song Yang , Wang Chuan-Kui , Chen Gang , Zhang Guang-Ping
Published: June 2021

A phthalocyanine-based multifunctional spintronic molecular device.
Identification of electronic descriptors for catalytic activity of transition-metal and non-metal doped MoS2
Authors: Xie Zijuan , Huang Xiang , Zhang Zhe , Xu Hu
Published: June 2021

A universal scaling relationship between H binding energy and anion p-band center of doped MoS2, MoSe2 and MoTe2.
Surface modification of titanium carbide MXene monolayers (Ti2C and Ti3C2) via chalcogenide and halogenide atoms
Authors: Faraji M. , Bafekry A. , Fadlallah M. M. , Molaei F. , Hieu N. N. , Qian P. , Ghergherehchi M. , Gogova D.
Published: June 2021

Inspired by the recent successful growth of Ti2C and Ti3C2 monolayers, here, we investigate the structural, electronic, and mechanical properties of functionalized Ti2C and Ti3C2 monolayers with chalcogenide and halogenide atoms by means of density functional theory calculations.
Self-folding and self-scrolling mechanisms of edge-deformed graphene sheets: a molecular dynamics study
Authors: Pereira Junior Marcelo Lopes , Ribeiro Junior Luiz Antonio
Published: June 2021

Graphene-based nanofolds (GNFs) are edge-connected 2D stacked monolayers that originate from single-layer graphene.
The tug of war between Al3+ and Na+ for order–disorder transitions in lipid-A membranes
Authors: Messias Andresa , Santos Denys E. S. , Pontes Frederico J. S. , Soares Thereza A.
Published: June 2021

Lipid-A can exhibit antagonist/agonist immunomodulatory properties depending on its chemical compostion. Computational simulations provide insights into the role of Al3+ and Na+ cations on the physical properties of lipid-A aggregates, and guidance in the development of vaccine adjuvants capable of boosting the immune system with decreased reactogenicity.