bluuebunny/crossref_metadata_2025_split huggingface dataset:
Possible stochastic sex determination in Bursaphelenchus nematodes
Authors: Shinya Ryoji , Sun Simo , Dayi Mehmet , Tsai Isheng Jason , Miyama Atsushi , Chen Anthony Fu , Hasegawa Koichi , Antoshechkin Igor , Kikuchi Taisei , Sternberg Paul W. 
Published: May 2022

AbstractSex determination mechanisms evolve surprisingly rapidly, yet little is known in the large nematode phylum other than for Caenorhabditis elegans, which relies on chromosomal XX-XO sex determination and a dosage compensation mechanism. Here we analyze by sex-specific genome sequencing and genetic analysis sex determination in two fungal feeding/plant-parasitic Bursaphelenchus nematodes and find that their sex differentiation is more likely triggered by random, epigenetic regulation than by more well-known mechanisms of chromosomal or environmental sex determination. There is no detectable difference in male and female chromosomes, nor any linkage to sexual phenotype. Moreover, the protein sets of these nematodes lack genes involved in X chromosome dosage counting or compensation. By contrast, our genetic screen for sex differentiation mutants identifies a Bursaphelenchus ortholog of tra-1, the major output of the C. elegans sex determination cascade. Nematode sex determination pathways might have evolved by “bottom-up” accretion from the most downstream regulator, tra-1.
Genetic analyses identify pleiotropy and causality for blood proteins and highlight Wnt/β-catenin signalling in migraine
Authors: Tanha Hamzeh M. ,   The International Headache Genetics Consortium, Nyholt Dale R. , Nyholt Dale R. 
Published: May 2022

AbstractMigraine is a common complex disorder with a significant polygenic SNP heritability ($${h}_{{SNP}}^{2}$$hSNP2). Here we utilise genome-wide association study (GWAS) summary statistics to study pleiotropy between blood proteins and migraine under the polygenic model. We estimate$${h}_{{SNP}}^{2}$$hSNP2for 4625 blood protein GWASs and identify 325 unique proteins with a significant$${h}_{{SNP}}^{2}$$hSNP2for use in subsequent genetic analyses. Pleiotropy analyses link 58 blood proteins to migraine risk at genome-wide, gene and/or single-nucleotide polymorphism levels—suggesting shared genetic influences or causal relationships. Notably, the identified proteins are largely distinct from migraine GWAS loci. We show that higher levels of DKK1 and PDGFB, and lower levels of FARS2, GSTA4 and CHIC2 proteins have a significant causal effect on migraine. The risk-increasing effect of DKK1 is particularly interesting—indicating a role for downregulation of β-catenin-dependent Wnt signalling in migraine risk, suggesting Wnt activators that restore Wnt/β-catenin signalling in brain could represent therapeutic tools against migraine.
Unlocking the functional potential of polyploid yeasts
Authors: Mozzachiodi Simone , Krogerus Kristoffer , Gibson Brian , Nicolas Alain , Liti Gianni 
Published: May 2022

AbstractBreeding and domestication have generated widely exploited crops, animals and microbes. However, many Saccharomyces cerevisiae industrial strains have complex polyploid genomes and are sterile, preventing genetic improvement strategies based on breeding. Here, we present a strain improvement approach based on the budding yeasts’ property to promote genetic recombination when meiosis is interrupted and cells return-to-mitotic-growth (RTG). We demonstrate that two unrelated sterile industrial strains with complex triploid and tetraploid genomes are RTG-competent and develop a visual screening for easy and high-throughput identification of recombined RTG clones based on colony phenotypes. Sequencing of the evolved clones reveal unprecedented levels of RTG-induced genome-wide recombination. We generate and extensively phenotype a RTG library and identify clones with superior biotechnological traits. Thus, we propose the RTG-framework as a fully non-GMO workflow to rapidly improve industrial yeasts that can be easily brought to the market.
A rare variant analysis framework using public genotype summary counts to prioritize disease-predisposition genes
Authors: Chen Wenan , Wang Shuoguo , Tithi Saima Sultana , Ellison David W. , Schaid Daniel J. , Wu Gang 
Published: May 2022

AbstractSequencing cases without matched healthy controls hinders prioritization of germline disease-predisposition genes. To circumvent this problem, genotype summary counts from public data sets can serve as controls. However, systematic inflation and false positives can arise if confounding factors are not controlled. We propose a framework,consistent summarycounts basedrarevariant burden test (CoCoRV), to address these challenges. CoCoRV implements consistent variant quality control and filtering, ethnicity-stratified rare variant association test, accurate estimation of inflation factors, powerful FDR control, and detection of rare variant pairs in high linkage disequilibrium. When we applied CoCoRV to pediatric cancer cohorts, the top genes identified were cancer-predisposition genes. We also applied CoCoRV to identify disease-predisposition genes in adult brain tumors and amyotrophic lateral sclerosis. Given that potential confounding factors were well controlled after applying the framework, CoCoRV provides a cost-effective solution to prioritizing disease-risk genes enriched with rare pathogenic variants.
On-chip nanophotonic topological rainbow
Authors: Lu Cuicui , Sun Yi-Zhi , Wang Chenyang , Zhang Hongyu , Zhao Wen , Hu Xiaoyong , Xiao Meng , Ding Wei , Liu Yong-Chun , Chan C. T. 
Published: May 2022

AbstractThe era of Big Data requires nanophotonic chips to have large information processing capacity. Multiple frequency on-chip nanophotonic devices are highly desirable for density integration, but such devices are more susceptible to structural imperfection because of their nano-scale. Topological photonics provides a robust platform for next-generation nanophotonic chips. Here we give an experimental report of an on-chip nanophotonic topological rainbow realized by employing a translational deformation freedom as a synthetic dimension. The topological rainbow can separate, slow, and trap topological photonic states of different frequencies into different positions. A homemade scattering scanning near-field optical microscope with high resolution is introduced to directly measure the topological rainbow effect of the silicon-based photonic chip. The topological rainbow based on synthetic dimension have no restrictions for optical lattice types, symmetries, materials, wavelength band, and is easy for on-chip integration. This work builds a bridge between silicon chip technologies and topological photonics.
Discovery and characterization of a terpene biosynthetic pathway featuring a norbornene-forming Diels-Alderase
Authors: Sun Zuodong , Jamieson Cooper S. , Ohashi Masao , Houk K. N. , Tang Yi 
Published: May 2022

AbstractPericyclases, enzymes that catalyze pericyclic reactions, form an expanding family of enzymes that have biocatalytic utility. Despite the increasing number of pericyclases discovered, the Diels-Alder cyclization between a cyclopentadiene and an olefinic dienophile to form norbornene, which is among the best-studied cycloadditions in synthetic chemistry, has surprisingly no enzymatic counterpart to date. Here we report the discovery of a pathway featuring a norbornene synthase SdnG for the biosynthesis of sordaricin-the terpene precursor of antifungal natural product sordarin. Full reconstitution of sordaricin biosynthesis reveals a concise oxidative strategy used by Nature to transform an entirely hydrocarbon precursor into the highly functionalized substrate of SdnG for intramolecular Diels-Alder cycloaddition. SdnG generates the norbornene core of sordaricin and accelerates this reaction to suppress host-mediated redox modifications of the activated dienophile. Findings from this work expand the scopes of pericyclase-catalyzed reactions and P450-mediated terpene maturation.
Water coordinated on Cu(I)-based catalysts is the oxygen source in CO2 reduction to CO
Authors: Zheng Yajun , Yao Hedan , Di Ruinan , Xiang Zhicheng , Wang Qiang , Lu Fangfang , Li Yu , Yang Guangxing , Ma Qiang , Zhang Zhiping 
Published: May 2022

AbstractCatalytic reduction of CO2 over Cu-based catalysts can produce various carbon-based products such as the critical intermediate CO, yet significant challenges remain in shedding light on the underlying mechanisms. Here, we develop a modified triple-stage quadrupole mass spectrometer to monitor the reduction of CO2 to CO in the gas phase online. Our experimental observations reveal that the coordinated H2O on Cu(I)-based catalysts promotes CO2 adsorption and reduction to CO, and the resulting efficiencies are two orders of magnitude higher than those without H2O. Isotope-labeling studies render compelling evidence that the O atom in produced CO originates from the coordinated H2O on catalysts, rather than CO2 itself. Combining experimental observations and computational calculations with density functional theory, we propose a detailed reaction mechanism of CO2 reduction to CO over Cu(I)-based catalysts with coordinated H2O. This study offers an effective method to reveal the vital roles of H2O in promoting metal catalysts to CO2 reduction.
3D chromatin remodelling in the germ line modulates genome evolutionary plasticity
Authors: Álvarez-González Lucía , Burden Frances , Doddamani Dadakhalandar , Malinverni Roberto , Leach Emma , Marín-García Cristina , Marín-Gual Laia , Gubern Albert , Vara Covadonga , Paytuví-Gallart Andreu , Buschbeck Marcus , Ellis Peter J. I. , Farré Marta , Ruiz-Herrera Aurora 
Published: May 2022

AbstractChromosome folding has profound impacts on gene regulation, whose evolutionary consequences are far from being understood. Here we explore the relationship between 3D chromatin remodelling in mouse germ cells and evolutionary changes in genome structure. Using a comprehensive integrative computational analysis, we (i) reconstruct seven ancestral rodent genomes analysing whole-genome sequences of 14 species representatives of the major phylogroups, (ii) detect lineage-specific chromosome rearrangements and (iii) identify the dynamics of the structural and epigenetic properties of evolutionary breakpoint regions (EBRs) throughout mouse spermatogenesis. Our results show that EBRs are devoid of programmed meiotic DNA double-strand breaks (DSBs) and meiotic cohesins in primary spermatocytes, but are associated in post-meiotic cells with sites of DNA damage and functional long-range interaction regions that recapitulate ancestral chromosomal configurations. Overall, we propose a model that integrates evolutionary genome reshuffling with DNA damage response mechanisms and the dynamic spatial genome organisation of germ cells.
Metabolite trafficking enables membrane-impermeable-terpene secretion by yeast
Authors: Son So-Hee , Kim Jae-Eung , Park Gyuri , Ko Young-Joon , Sung Bong Hyun , Seo Jongcheol , Oh Seung Soo , Lee Ju Young 
Published: May 2022

AbstractMetabolites are often unable to permeate cell membranes and are thus accumulated inside cells. We investigate whether engineered microbes can exclusively secrete intracellular metabolites because sustainable metabolite secretion holds a great potential for mass-production of high-value chemicals in an efficient and continuous manner. In this study, we demonstrate a synthetic pathway for a metabolite trafficking system that enables lipophilic terpene secretion by yeast cells. When metabolite-binding proteins are tagged with signal peptides, metabolite trafficking is highly achievable; loaded metabolites can be precisely delivered to a desired location within or outside the cell. As a proof of concept, we systematically couple a terpene-binding protein with an export signal peptide and subsequently demonstrate efficient, yet selective terpene secretion by yeast (~225 mg/L for squalene and ~1.6 mg/L for β-carotene). Other carrier proteins can also be readily fused with desired signal peptides, thereby tailoring different metabolite trafficking pathways in different microbes. To the best of our knowledge, this is the most efficient cognate pathway for metabolite secretion by microorganisms.
Atomic overlayer of permeable microporous cuprous oxide on palladium promotes hydrogenation catalysis
Authors: Liu Kunlong , Jiang Lizhi , Huang Wugen , Zhu Guozhen , Zhang Yue-Jiao , Xu Chaofa , Qin Ruixuan , Liu Pengxin , Hu Chengyi , Wang Jingjuan , Li Jian-Feng , Yang Fan , Fu Gang , Zheng Nanfeng 
Published: May 2022

AbstractThe interfacial sites of metal-support interface have been considered to be limited to the atomic region of metal/support perimeter, despite their high importance in catalysis. By using single-crystal surface and nanocrystal as model catalysts, we now demonstrate that the overgrowth of atomic-thick Cu2O on metal readily creates a two-dimensional (2D) microporous interface with Pd to enhance the hydrogenation catalysis. With the hydrogenation confined within the 2D Cu2O/Pd interface, the catalyst exhibits outstanding activity and selectivity in the semi-hydrogenation of alkynes. Alloying Cu(0) with Pd under the overlayer is the major contributor to the enhanced activity due to the electronic modulation to weaken the H adsorption. Moreover, the boundary or defective sites on the Cu2O overlayer can be passivated by terminal alkynes, reinforcing the chemical stability of Cu2O and thus the catalytic stability toward hydrogenation. The deep understanding allows us to extend the interfacial sites far beyond the metal/support perimeter and provide new vectors for catalyst optimization through 2D interface interaction.
Subnanometric Cu clusters on atomically Fe-doped MoO2 for furfural upgrading to aviation biofuels
Authors: Zhao Xin , Wang Fengliang , Kong Xiangpeng , Fang Ruiqi , Li Yingwei 
Published: May 2022

AbstractSingle cluster catalysts (SCCs) are considered as versatile boosters in heterogeneous catalysis due to their modifiable single cluster sites and supports. In this work, we report subnanometric Cu clusters dispersed on Fe-doped MoO2 support for biomass-derived furfural upgrading. Systematical characterizations suggest uniform Cu clusters (composing four Cu atoms in average) are homogeneously immobilized on the atomically Fe-doped ultrafine MoO2 nanocrystals (Cu4/Fe0.3Mo0.7O2@C). The atomic doping of Fe into MoO2 leads to significantly modified electronic structure and consequently charge redistribution inside the supported Cu clusters. The as-prepared Cu4/Fe0.3Mo0.7O2@C shows superior catalytic performance in the oxidative coupling of furfural with C3~C10 primary/secondary alcohols to produce C8~C15 aldehydes/ketones (aviation biofuel intermediates), outperforming the conventionally prepared counterparts. DFT calculations and control experiments are further carried out to interpret the structural and compositional merits of Cu4/Fe0.3Mo0.7O2@C in the oxidative coupling reaction, and elucidate the reaction pathway and related intermediates.
Patatin-like phospholipase CapV in Escherichia coli - morphological and physiological effects of one amino acid substitution
Authors: Li Fengyang , Cao Lianying , Bähre Heike , Kim Soo-Kyoung , Schroeder Kristen , Jonas Kristina , Koonce Kira , Mekonnen Solomon A. , Mohanty Soumitra , Bai Fengwu , Brauner Annelie , Lee Vincent T. , Rohde Manfred , Römling Ute 
Published: May 2022

AbstractIn rod-shaped bacteria, morphological plasticity occurs in response to stress, which blocks cell division to promote filamentation. We demonstrate here that overexpression of the patatin-like phospholipase variant CapVQ329R, but not CapV, causes pronouncedsulA-independent pyridoxine-inhibited cell filamentation in theEscherichia coliK-12-derivative MG1655 associated with restriction of flagella production and swimming motility. Conserved amino acids in canonical patatin-like phospholipase A motifs, but not the nucleophilic serine, are required to mediate CapVQ329Rphenotypes. Furthermore, CapVQ329Rproduction substantially alters the lipidome and colony morphotype including rdar biofilm formation with modulation of the production of the biofilm activator CsgD, and affects additional bacterial traits such as the efficiency of phage infection and antimicrobial susceptibility. Moreover, genetically diverse commensal and pathogenicE. colistrains andSalmonella typhimuriumresponded with cell filamentation and modulation in colony morphotype formation to CapVQ329Rexpression. In conclusion, this work identifies the CapV variant CapVQ329Ras a pleiotropic regulator, emphasizes a scaffold function for patatin-like phospholipases, and highlights the impact of the substitution of a single conserved amino acid for protein functionality and alteration of host physiology.
A prebiotically plausible scenario of an RNA–peptide world
Authors: Müller Felix , Escobar Luis , Xu Felix , Węgrzyn Ewa , Nainytė Milda , Amatov Tynchtyk , Chan Chun‐Yin , Pichler Alexander , Carell Thomas 
Published: May 2022

AbstractThe RNA world concept1 is one of the most fundamental pillars of the origin of life theory2–4. It predicts that life evolved from increasingly complex self-replicating RNA molecules1,2,4. The question of how this RNA world then advanced to the next stage, in which proteins became the catalysts of life and RNA reduced its function predominantly to information storage, is one of the most mysterious chicken-and-egg conundrums in evolution3–5. Here we show that non-canonical RNA bases, which are found today in transfer and ribosomal RNAs6,7, and which are considered to be relics of the RNA world8–12, are able to establish peptide synthesis directly on RNA. The discovered chemistry creates complex peptide-decorated RNA chimeric molecules, which suggests the early existence of an RNA–peptide world13 from which ribosomal peptide synthesis14 may have emerged15,16. The ability to grow peptides on RNA with the help of non-canonical vestige nucleosides offers the possibility of an early co-evolution of covalently connected RNAs and peptides13,17,18, which then could have dissociated at a higher level of sophistication to create the dualistic nucleic acid–protein world that is the hallmark of all life on Earth.
Fundamental immune–oncogenicity trade-offs define driver mutation fitness
Authors: Hoyos David , Zappasodi Roberta , Schulze Isabell , Sethna Zachary , de Andrade Kelvin César , Bajorin Dean F. , Bandlamudi Chaitanya , Callahan Margaret K. , Funt Samuel A. , Hadrup Sine R. , Holm Jeppe S. , Rosenberg Jonathan E. , Shah Sohrab P. , Vázquez-García Ignacio , Weigelt Britta , Wu Michelle , Zamarin Dmitriy , Campitelli Laura F. , Osborne Edward J. , Klinger Mark , Robins Harlan S. , Khincha Payal P. , Savage Sharon A. , Balachandran Vinod P. , Wolchok Jedd D. , Hellmann Matthew D. , Merghoub Taha , Levine Arnold J. , Łuksza Marta , Greenbaum Benjamin D. 
Published: May 2022

AbstractMissense driver mutations in cancer are concentrated in a few hotspots1. Various mechanisms have been proposed to explain this skew, including biased mutational processes2, phenotypic differences3–6 and immunoediting of neoantigens7,8; however, to our knowledge, no existing model weighs the relative contribution of these features to tumour evolution. We propose a unified theoretical ‘free fitness’ framework that parsimoniously integrates multimodal genomic, epigenetic, transcriptomic and proteomic data into a biophysical model of the rate-limiting processes underlying the fitness advantage conferred on cancer cells by driver gene mutations. Focusing on TP53, the most mutated gene in cancer1, we present an inference of mutant p53 concentration and demonstrate that TP53 hotspot mutations optimally solve an evolutionary trade-off between oncogenic potential and neoantigen immunogenicity. Our model anticipates patient survival in The Cancer Genome Atlas and patients with lung cancer treated with immunotherapy as well as the age of tumour onset in germline carriers of TP53 variants. The predicted differential immunogenicity between hotspot mutations was validated experimentally in patients with cancer and in a unique large dataset of healthy individuals. Our data indicate that immune selective pressure on TP53 mutations has a smaller role in non-cancerous lesions than in tumours, suggesting that targeted immunotherapy may offer an early prophylactic opportunity for the former. Determining the relative contribution of immunogenicity and oncogenic function to the selective advantage of hotspot mutations thus has important implications for both precision immunotherapies and our understanding of tumour evolution.
Extricating human tumour immune alterations from tissue inflammation
Authors: Mair Florian , Erickson Jami R. , Frutoso Marie , Konecny Andrew J. , Greene Evan , Voillet Valentin , Maurice Nicholas J. , Rongvaux Anthony , Dixon Douglas , Barber Brittany , Gottardo Raphael , Prlic Martin 
Published: May 2022

AbstractImmunotherapies have achieved remarkable successes in the treatment of cancer, but major challenges remain1,2. An inherent weakness of current treatment approaches is that therapeutically targeted pathways are not restricted to tumours, but are also found in other tissue microenvironments, complicating treatment3,4. Despite great efforts to define inflammatory processes in the tumour microenvironment, the understanding of tumour-unique immune alterations is limited by a knowledge gap regarding the immune cell populations in inflamed human tissues. Here, in an effort to identify such tumour-enriched immune alterations, we used complementary single-cell analysis approaches to interrogate the immune infiltrate in human head and neck squamous cell carcinomas and site-matched non-malignant, inflamed tissues. Our analysis revealed a large overlap in the composition and phenotype of immune cells in tumour and inflamed tissues. Computational analysis identified tumour-enriched immune cell interactions, one of which yields a large population of regulatory T (Treg) cells that is highly enriched in the tumour and uniquely identified among all haematopoietically-derived cells in blood and tissue by co-expression of ICOS and IL-1 receptor type 1 (IL1R1). We provide evidence that these intratumoural IL1R1+ Treg cells had responded to antigen recently and demonstrate that they are clonally expanded with superior suppressive function compared with IL1R1− Treg cells. In addition to identifying extensive immunological congruence between inflamed tissues and tumours as well as tumour-specific changes with direct disease relevance, our work also provides a blueprint for extricating disease-specific changes from general inflammation-associated patterns.
Structural basis of sodium-dependent bile salt uptake into the liver
Authors: Goutam Kapil , Ielasi Francesco S. , Pardon Els , Steyaert Jan , Reyes Nicolas 
Published: May 2022

AbstractThe liver takes up bile salts from blood to generate bile, enabling absorption of lipophilic nutrients and excretion of metabolites and drugs1. Human Na+–taurocholate co-transporting polypeptide (NTCP) is the main bile salt uptake system in liver. NTCP is also the cellular entry receptor of human hepatitis B and D viruses2,3 (HBV/HDV), and has emerged as an important target for antiviral drugs4. However, the molecular mechanisms underlying NTCP transport and viral receptor functions remain incompletely understood. Here we present cryo-electron microscopy structures of human NTCP in complexes with nanobodies, revealing key conformations of its transport cycle. NTCP undergoes a conformational transition opening a wide transmembrane pore that serves as the transport pathway for bile salts, and exposes key determinant residues for HBV/HDV binding to the outside of the cell. A nanobody that stabilizes pore closure and inward-facing states impairs recognition of the HBV/HDV receptor-binding domain preS1, demonstrating binding selectivity of the viruses for open-to-outside over inward-facing conformations of the NTCP transport cycle. These results provide molecular insights into NTCP ‘gated-pore’ transport and HBV/HDV receptor recognition mechanisms, and are expected to help with development of liver disease therapies targeting NTCP.