bluuebunny/crossref_metadata_2025 huggingface dataset:
Closure Investigation on Cloud Condensation Nuclei Ability of Processed Anthropogenic Aerosols
Authors: Hu Dawei , Liu Dantong , Zhao Delong , Yu Chenjie , Liu Quan , Tian Ping , Bi Kai , Ding Shuo , Hu Kang , Wang Fei , Wu Yangzhou , Wu Yunfei , Kong Shaofei , Zhou Wei , He Hui , Huang Mengyu , Ding Deping
Published: July 2020

Whether the cloud condensation nuclei (CCN) ability of aerosol could be predicted by compositions has been long debated. Measurements of submicron aerosol compositions and size‐resolved CCN activation fraction were conducted at a mountain site (1,344 m) near Beijing region during wintertime. The site is influenced in the noon‐afternoon by ground anthropogenic sources through convective mixing (CM) and for certain period received aged pollutants by regional advection (RA). By comparing the measured CCN‐derived hygroscopicity parameter (κCCNc) with that predicted using chemical composition in bulk (κchem), we found for CM period, κchem overpredicted κCCNc by 71 ± 11% (25 ± 13%) at SS = 0.1% (0.3%); whereas for RA‐only period, κchem underpredicted by 13 ± 6% (18 ± 11%) at SS = 0.1% (0.3%). The former, representing fresher aerosols in smaller size, could be explained by not considering the size‐resolved composition, as the bulk measurement mainly reflects the features of larger particle. The latter is proved to result from the depression of droplet surface tension by potential surface‐active organics and the possible liquid‐liquid phase separation occurring at moderate RH, and a use of depressed surface tension (than pure water) of 0.063 ± 0.002 J m−2 would reach an agreement. We propose that a hybrid approach combining size‐resolved composition and reduced surface tension, for fresher and aged sources, respectively, should improve the estimation of aerosol CCN ability.
FBXO45 is a potential therapeutic target for cancer therapy
Authors: Lin Min , Wang Zhi-wei , Zhu Xueqiong
Published: July 2020

FBXO protein 45 (FBXO45), a substrate-recognition subunit of E3 ligases, has been characterised to have pivotal roles in many human diseases, including nervous system diseases, inflammatory diseases and human malignancies. In this article, we describe the expression of FBXO45 in several types of human tumour specimens and highlight the downstream substrates of FBXO45. Moreover, the biological functions of FBXO45 in the regulation of proliferation, apoptosis, the cell cycle and metastasis are mentioned. Furthermore, we describe that the expression level of FBXO45 is regulated by several upstream factors such as miR-27a, Hey1, m6A and the lncRNA RP11. As FBXO45 has a critical role in tumorigenesis and progression, FBXO45 might be a novel therapeutic target for cancer treatment.
CryoEM structure of the tegumented capsid of Epstein-Barr virus
Authors: Li Zhihai , Zhang Xiao , Dong Lili , Pang Jingjing , Xu Miao , Zhong Qian , Zeng Mu-Sheng , Yu Xuekui
Published: July 2020

Epstein-Barr virus (EBV) is the primary cause of infectious mononucleosis and has been shown to be closely associated with various malignancies. Here, we present a complete atomic model of EBV, including the icosahedral capsid, the dodecameric portal and the capsid-associated tegument complex (CATC). Our in situ portal from the tegumented capsid adopts a closed conformation with its channel valve holding the terminal viral DNA and with its crown region firmly engaged by three layers of ring-like dsDNA, which, together with the penton flexibility, effectively alleviates the capsid inner pressure placed on the portal cap. In contrast, the CATCs, through binding to the flexible penton vertices in a stoichiometric manner, accurately increase the inner capsid pressure to facilitate the pressure-driven genome delivery. Together, our results provide important insights into the mechanism by which the EBV capsid, portal, packaged genome and the CATCs coordinately achieve a pressure balance to simultaneously benefit both viral genome retention and ejection.
Observation of Weyl fermions in a magnetic non-centrosymmetric crystal
Authors: Sanchez Daniel S. , Chang Guoqing , Belopolski Ilya , Lu Hong , Yin Jia-Xin , Alidoust Nasser , Xu Xitong , Cochran Tyler A. , Zhang Xiao , Bian Yi , Zhang Songtian S. , Liu Yi-Yuan , Ma Jie , Bian Guang , Lin Hsin , Xu Su-Yang , Jia Shuang , Hasan M. Zahid
Published: July 2020

The absence of inversion symmetry in non-centrosymmetric materials has a fundamental role in the emergence of a vast number of fascinating phenomena, like ferroelectricity, second harmonic generation, and Weyl fermions. The removal of time-reversal symmetry in such systems further extends the variety of observable magneto-electric and topological effects. Here we report the striking topological properties in the non-centrosymmetric spin-orbit magnet PrAlGe by combining spectroscopy and transport measurements. By photoemission spectroscopy below the Curie temperature, we observe topological Fermi arcs that correspond to projected topological charges of ±1 in the surface Brillouin zone. In the bulk, we observe the linear energy-dispersion of the Weyl fermions. We further observe a large anomalous Hall response in our magneto-transport measurements, which is understood to arise from diverging bulk Berry curvature fields associated with the Weyl band structure. These results establish a novel Weyl semimetal phase in magnetic non-centrosymmetric PrAlGe.
Increasing trends in regional heatwaves
Authors: Perkins-Kirkpatrick S. E. , Lewis S. C.
Published: July 2020

Heatwaves have increased in intensity, frequency and duration, with these trends projected to worsen under enhanced global warming. Understanding regional heatwave trends has critical implications for the biophysical and human systems they impact. Until now a comprehensive assessment of regional observed changes was hindered by the range of metrics employed, underpinning datasets, and time periods examined. Here, using the Berkeley Earth temperature dataset and key heatwave metrics, we systematically examine regional and global observed heatwave trends. In almost all regions, heatwave frequency demonstrates the most rapid and significant change. A measure of cumulative heat shows significant increases almost everywhere since the 1950s, mainly driven by heatwave days. Trends in heatwave frequency, duration and cumulative heat have accelerated since the 1950s, and due to the high influence of variability we recommend regional trends are assessed over multiple decades. Our results provide comparable regional observed heatwave trends, on spatial and temporal scales necessary for understanding impacts.
Long-term droughts may drive drier tropical forests towards increased functional, taxonomic and phylogenetic homogeneity
Authors: Aguirre-Gutiérrez Jesús , Malhi Yadvinder , Lewis Simon L. , Fauset Sophie , Adu-Bredu Stephen , Affum-Baffoe Kofi , Baker Timothy R. , Gvozdevaite Agne , Hubau Wannes , Moore Sam , Peprah Theresa , Ziemińska Kasia , Phillips Oliver L. , Oliveras Imma
Published: July 2020

Tropical ecosystems adapted to high water availability may be highly impacted by climatic changes that increase soil and atmospheric moisture deficits. Many tropical regions are experiencing significant changes in climatic conditions, which may induce strong shifts in taxonomic, functional and phylogenetic diversity of forest communities. However, it remains unclear if and to what extent tropical forests are shifting in these facets of diversity along climatic gradients in response to climate change. Here, we show that changes in climate affected all three facets of diversity in West Africa in recent decades. Taxonomic and functional diversity increased in wetter forests but tended to decrease in forests with drier climate. Phylogenetic diversity showed a large decrease along a wet-dry climatic gradient. Notably, we find that all three facets of diversity tended to be higher in wetter forests. Drier forests showed functional, taxonomic and phylogenetic homogenization. Understanding how different facets of diversity respond to a changing environment across climatic gradients is essential for effective long-term conservation of tropical forest ecosystems.
Comprehensive identification of mRNA isoforms reveals the diversity of neural cell-surface molecules with roles in retinal development and disease
Authors: Ray Thomas A. , Cochran Kelly , Kozlowski Chris , Wang Jingjing , Alexander Graham , Cady Martha A. , Spencer William J. , Ruzycki Philip A. , Clark Brian S. , Laeremans Annelies , He Ming-Xiao , Wang Xiaoming , Park Emily , Hao Ying , Iannaccone Alessandro , Hu Gary , Fedrigo Olivier , Skiba Nikolai P. , Arshavsky Vadim Y. , Kay Jeremy N.
Published: July 2020

Genes encoding cell-surface proteins control nervous system development and are implicated in neurological disorders. These genes produce alternative mRNA isoforms which remain poorly characterized, impeding understanding of how disease-associated mutations cause pathology. Here we introduce a strategy to define complete portfolios of full-length isoforms encoded by individual genes. Applying this approach to neural cell-surface molecules, we identify thousands of unannotated isoforms expressed in retina and brain. By mass spectrometry we confirm expression of newly-discovered proteins on the cell surface in vivo. Remarkably, we discover that the major isoform of a retinal degeneration gene, CRB1, was previously overlooked. This CRB1 isoform is the only one expressed by photoreceptors, the affected cells in CRB1 disease. Using mouse mutants, we identify a function for this isoform at photoreceptor-glial junctions and demonstrate that loss of this isoform accelerates photoreceptor death. Therefore, our isoform identification strategy enables discovery of new gene functions relevant to disease.
Characterization of an alternative BAK-binding site for BH3 peptides
Authors: Ye Kaiqin , Meng Wei X. , Sun Hongbin , Wu Bo , Chen Meng , Pang Yuan-Ping , Gao Jia , Wang Hongzhi , Wang Junfeng , Kaufmann Scott H. , Dai Haiming
Published: July 2020

Many cellular stresses are transduced into apoptotic signals through modification or up-regulation of the BH3-only subfamily of BCL2 proteins. Through direct or indirect mechanisms, these proteins activate BAK and BAX to permeabilize the mitochondrial outer membrane. While the BH3-only proteins BIM, PUMA, and tBID have been confirmed to directly activate BAK through its canonical BH3 binding groove, whether the BH3-only proteins BMF, HRK or BIK can directly activate BAK is less clear. Here we show that BMF and HRK bind and directly activate BAK. Through NMR studies, site-directed mutagenesis, and advanced molecular dynamics simulations, we also find that BAK activation by BMF and possibly HRK involves a previously unrecognized binding groove formed by BAK α4, α6, and α7 helices. Alterations in this groove decrease the ability of BMF and HRK to bind BAK, permeabilize membranes and induce apoptosis, suggesting a potential role for this BH3-binding site in BAK activation.
An inherently infinite-dimensional quantum correlation
Authors: Coladangelo Andrea , Stark Jalex
Published: July 2020

Bell’s theorem, a landmark result in the foundations of physics, establishes that quantum mechanics is a non-local theory. It asserts, in particular, that two spatially separated, but entangled, quantum systems can be correlated in a way that cannot be mimicked by classical systems. A direct operational consequence of Bell’s theorem is the existence of statistical tests which can detect the presence of entanglement. Remarkably, certain correlations not only witness entanglement, but they give quantitative bounds on the minimum dimension of quantum systems attaining them. In this work, we show that there exists a correlation which is not attainable by quantum systems of any arbitrary finite dimension, but is attained exclusively by infinite-dimensional quantum systems (such as infinite-level systems arising from quantum harmonic oscillators). This answers the long-standing open question about the existence of a finite correlation witnessing infinite entanglement.
Mechanistic insights into chromatin targeting by leukemic NUP98-PHF23 fusion
Authors: Zhang Yi , Guo Yiran , Gough Sheryl M. , Zhang Jinyong , Vann Kendra R. , Li Kuai , Cai Ling , Shi Xiaobing , Aplan Peter D. , Wang Gang Greg , Kutateladze Tatiana G.
Published: July 2020

Chromosomal NUP98-PHF23 translocation is associated with an aggressive form of acute myeloid leukemia (AML) and poor survival rate. Here, we report the molecular mechanisms by which NUP98-PHF23 recognizes the histone mark H3K4me3 and is inhibited by small molecule compounds, including disulfiram that directly targets the PHD finger of PHF23 (PHF23PHD). Our data support a critical role for the PHD fingers of NUP98-PHF23, and related NUP98-KDM5A and NUP98-BPTF fusions in driving leukemogenesis, and demonstrate that blocking this interaction in NUP98-PHF23 expressing AML cells leads to cell death through necrotic and late apoptosis pathways. An overlap of NUP98-KDM5A oncoprotein binding sites and H3K4me3-positive loci at the Hoxa/b gene clusters and Meis1 in ChIP-seq, together with NMR analysis of the H3K4me3-binding sites of the PHD fingers from PHF23, KDM5A and BPTF, suggests a common PHD finger-dependent mechanism that promotes leukemogenesis by this type of NUP98 fusions. Our findings highlight the direct correlation between the abilities of NUP98-PHD finger fusion chimeras to associate with H3K4me3-enriched chromatin and leukemic transformation.
Intellectual disability-associated UNC80 mutations reveal inter-subunit interaction and dendritic function of the NALCN channel complex
Authors: Wie Jinhong , Bharthur Apoorva , Wolfgang Morgan , Narayanan Vinodh , Ramsey Keri ,   C4RCD Research Group, Belnap Newell , Claasen Ana , Courtright Amanda , de Both Matt , Huentelman Matthew , Rangasamy Sampathkumar , Richholt Ryan , Schrauwen Isabelle , Siniard Ashley L. , Szelinger Szabolics , Aranda Kimberly , Zhang Qi , Zhou Yandong , Ren Dejian
Published: July 2020

The sodium-leak channel NALCN forms a subthreshold sodium conductance that controls the resting membrane potentials of neurons. The auxiliary subunits of the channel and their functions in mammals are largely unknown. In this study, we demonstrate that two large proteins UNC80 and UNC79 are subunits of the NALCN complex. UNC80 knockout mice are neonatal lethal. The C-terminus of UNC80 contains a domain that interacts with UNC79 and overcomes a soma-retention signal to achieve dendritic localization. UNC80 lacking this domain, as found in human patients, still supports whole-cell NALCN currents but lacks dendritic localization. Our results establish the subunit composition of the NALCN complex, uncover the inter-subunit interaction domains, reveal the functional significance of regulation of dendritic membrane potential by the sodium-leak channel complex, and provide evidence supporting that genetic variations found in individuals with intellectual disability are the causes for the phenotype observed in patients.
Antagonistic odor interactions in olfactory sensory neurons are widespread in freely breathing mice
Authors: Zak Joseph D. , Reddy Gautam , Vergassola Massimo , Murthy Venkatesh N.
Published: July 2020

Odor landscapes contain complex blends of molecules that each activate unique, overlapping populations of olfactory sensory neurons (OSNs). Despite the presence of hundreds of OSN subtypes in many animals, the overlapping nature of odor inputs may lead to saturation of neural responses at the early stages of stimulus encoding. Information loss due to saturation could be mitigated by normalizing mechanisms such as antagonism at the level of receptor-ligand interactions, whose existence and prevalence remains uncertain. By imaging OSN axon terminals in olfactory bulb glomeruli as well as OSN cell bodies within the olfactory epithelium in freely breathing mice, we find widespread antagonistic interactions in binary odor mixtures. In complex mixtures of up to 12 odorants, antagonistic interactions are stronger and more prevalent with increasing mixture complexity. Therefore, antagonism is a common feature of odor mixture encoding in OSNs and helps in normalizing activity to reduce saturation and increase information transfer.
C9orf72 arginine-rich dipeptide repeats inhibit UPF1-mediated RNA decay via translational repression
Authors: Sun Yu , Eshov Aziz , Zhou Jeffrey , Isiktas Atagun U. , Guo Junjie U.
Published: July 2020

Expansion of an intronic (GGGGCC)n repeat region within the C9orf72 gene is a main cause of familial amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). A hallmark of c9ALS/FTD is the accumulation of misprocessed RNAs, which are often targets of cellular RNA surveillance. Here, we show that RNA decay mechanisms involving upstream frameshift 1 (UPF1), including nonsense-mediated decay (NMD), are inhibited in c9ALS/FTD brains and in cultured cells expressing either of two arginine-rich dipeptide repeats (R-DPRs), poly(GR) and poly(PR). Mechanistically, although R-DPRs cause the recruitment of UPF1 to stress granules, stress granule formation is independent of NMD inhibition. Instead, NMD inhibition is primarily a result from global translational repression caused by R-DPRs. Overexpression of UPF1, but none of its NMD-deficient mutants, enhanced the survival of neurons treated by R-DPRs, suggesting that R-DPRs cause neurotoxicity in part by inhibiting cellular RNA surveillance.
De novo design of Au36(SR)24 nanoclusters
Authors: Liu Xu , Xu Wen Wu , Huang Xinyu , Wang Endong , Cai Xiao , Zhao Yue , Li Jin , Xiao Min , Zhang Chunfeng , Gao Yi , Ding Weiping , Zhu Yan
Published: July 2020

The discovery of atomically precise nanoclusters is generally unpredictable, and the rational synthesis of nanoclusters guided by the theoretical design is still in its infancy. Here we present a de novo design of Au36(SR)24 nanoclusters, from theoretical prediction to experimental synthesis and characterization of their physicochemical properties. The crystal structure of an Au36(SR)24 nanocluster perfectly matches the simulated structural pattern with Au4 tetrahedral units along a two-dimensional growth. The Au36(SR)24 nanocluster indeed differs from its structural isomer whose kernel is dissected in an Au4 tetrahedral manner along a one-dimensional growth. The structural isomerism in the Au36(SR)24 nanoclusters further induces distinct differences in ultrafast electron dynamics and chirality. This work will not only promote the atomically precise synthesis of nanoclusters enlightened by theoretical science, but also open up exciting opportunities for underpinning the widespread applications of structural isomers with atomic precision.
Heteroatom-bridged molecular belts as containers
Authors: Xie Jialin , Li Xia , Wang Shenghua , Li Anquan , Jiang Long , Zhu Kelong
Published: July 2020

Hoop-shaped or belt-like molecules have been fascinating not only due to their challenging synthesis, but also unique physical and chemical properties. The incorporation of heteroatoms (N, O, S, etc.) into these belts could alter both molecular structures and electronic properties which will lead to versatile applications, from advanced host-guest systems to functional materials. Despite numerous computational studies, the synthesis and characterization of heteroatom-bridged double-stranded molecular belts remains scarce. Here we report the synthesis, crystal structure, and host-guest chemistry of two novel heteroatom-bridged belt-like macrocycles composed of phenoxathiin. The bowl-shaped belt demonstrates a strong binding affinity (Ka = 3.6 × 109 M‒2) towards fullerene C60 and forms a 2:1 capsule-like complex with the aid of C‒H···S hydrogen bonds. The column-like belt can bind the cyclic guest [2,2]paracyclophane to form a ring-in-ring complex. The modular synthesis, structural specificity, and diverse host-guest chemistry of cyclophenoxathiins markedly expands the known chemistry of molecular belts.
Structural insight into mitochondrial β-barrel outer membrane protein biogenesis
Authors: Diederichs Kathryn A. , Ni Xiaodan , Rollauer Sarah E. , Botos Istvan , Tan Xiaofeng , King Martin S. , Kunji Edmund R. S. , Jiang Jiansen , Buchanan Susan K.
Published: July 2020

In mitochondria, β-barrel outer membrane proteins mediate protein import, metabolite transport, lipid transport, and biogenesis. The Sorting and Assembly Machinery (SAM) complex consists of three proteins that assemble as a 1:1:1 complex to fold β-barrel proteins and insert them into the mitochondrial outer membrane. We report cryoEM structures of the SAM complex from Myceliophthora thermophila, which show that Sam50 forms a 16-stranded transmembrane β-barrel with a single polypeptide-transport-associated (POTRA) domain extending into the intermembrane space. Sam35 and Sam37 are located on the cytosolic side of the outer membrane, with Sam35 capping Sam50, and Sam37 interacting extensively with Sam35. Sam35 and Sam37 each adopt a GST-like fold, with no functional, structural, or sequence similarity to their bacterial counterparts. Structural analysis shows how the Sam50 β-barrel opens a lateral gate to accommodate its substrates.
Pancreatic circulating tumor cell profiling identifies LIN28B as a metastasis driver and drug target
Authors: Franses Joseph W. , Philipp Julia , Missios Pavlos , Bhan Irun , Liu Ann , Yashaswini Chittampalli , Tai Eric , Zhu Huili , Ligorio Matteo , Nicholson Benjamin , Tassoni Elizabeth M. , Desai Niyati , Kulkarni Anupriya S. , Szabolcs Annamaria , Hong Theodore S. , Liss Andrew S. , Fernandez-del Castillo Carlos , Ryan David P. , Maheswaran Shyamala , Haber Daniel A. , Daley George Q. , Ting David T.
Published: July 2020

Pancreatic ductal adenocarcinoma (PDAC) lethality is due to metastatic dissemination. Characterization of rare, heterogeneous circulating tumor cells (CTCs) can provide insight into metastasis and guide development of novel therapies. Using the CTC-iChip to purify CTCs from PDAC patients for RNA-seq characterization, we identify three major correlated gene sets, with stemness genes LIN28B/KLF4, WNT5A, and LGALS3 enriched in each correlated gene set; only LIN28B CTC expression was prognostic. CRISPR knockout of LIN28B—an oncofetal RNA-binding protein exerting diverse effects via negative regulation of let-7 miRNAs and other RNA targets—in cell and animal models confers a less aggressive/metastatic phenotype. This correlates with de-repression of let-7 miRNAs and is mimicked by silencing of downstream let-7 target HMGA2 or chemical inhibition of LIN28B/let-7 binding. Molecular characterization of CTCs provides a unique opportunity to correlated gene set metastatic profiles, identify drivers of dissemination, and develop therapies targeting the “seeds” of metastasis.
Germline de novo mutation rates on exons versus introns in humans
Authors: Rodriguez-Galindo Miguel , Casillas Sònia , Weghorn Donate , Barbadilla Antonio
Published: July 2020

A main assumption of molecular population genetics is that genomic mutation rate does not depend on sequence function. Challenging this assumption, a recent study has found a reduction in the mutation rate in exons compared to introns in somatic cells, ascribed to an enhanced exonic mismatch repair system activity. If this reduction happens also in the germline, it can compromise studies of population genomics, including the detection of selection when using introns as proxies for neutrality. Here we compile and analyze published germline de novo mutation data to test if the exonic mutation rate is also reduced in germ cells. After controlling for sampling bias in datasets with diseased probands and extended nucleotide context dependency, we find no reduction in the mutation rate in exons compared to introns in the germline. Therefore, there is no evidence that enhanced exonic mismatch repair activity determines the mutation rate in germline cells.
Super-assembly of ER-phagy receptor Atg40 induces local ER remodeling at contacts with forming autophagosomal membranes
Authors: Mochida Keisuke , Yamasaki Akinori , Matoba Kazuaki , Kirisako Hiromi , Noda Nobuo N. , Nakatogawa Hitoshi
Published: July 2020

The endoplasmic reticulum (ER) is selectively degraded by autophagy (ER-phagy) through proteins called ER-phagy receptors. In Saccharomyces cerevisiae, Atg40 acts as an ER-phagy receptor to sequester ER fragments into autophagosomes by binding Atg8 on forming autophagosomal membranes. During ER-phagy, parts of the ER are morphologically rearranged, fragmented, and loaded into autophagosomes, but the mechanism remains poorly understood. Here we find that Atg40 molecules assemble in the ER membrane concurrently with autophagosome formation via multivalent interaction with Atg8. Atg8-mediated super-assembly of Atg40 generates highly-curved ER regions, depending on its reticulon-like domain, and supports packing of these regions into autophagosomes. Moreover, tight binding of Atg40 to Atg8 is achieved by a short helix C-terminal to the Atg8-family interacting motif, and this feature is also observed for mammalian ER-phagy receptors. Thus, this study significantly advances our understanding of the mechanisms of ER-phagy and also provides insights into organelle fragmentation in selective autophagy of other organelles.
Diverse interactions and ecosystem engineering can stabilize community assembly
Authors: Yeakel Justin D. , Pires Mathias M. , de Aguiar Marcus A. M. , O’Donnell James L. , Guimarães Paulo R. , Gravel Dominique , Gross Thilo
Published: July 2020

The complexity of an ecological community can be distilled into a network, where diverse interactions connect species in a web of dependencies. Species interact directly with each other and indirectly through environmental effects, however to our knowledge the role of these ecosystem engineers has not been considered in ecological network models. Here we explore the dynamics of ecosystem assembly, where species colonization and extinction depends on the constraints imposed by trophic, service, and engineering dependencies. We show that our assembly model reproduces many key features of ecological systems, such as the role of generalists during assembly, realistic maximum trophic levels, and increased nestedness with mutualistic interactions. We find that ecosystem engineering has large and nonlinear effects on extinction rates. While small numbers of engineers reduce stability by increasing primary extinctions, larger numbers of engineers increase stability by reducing primary extinctions and extinction cascade magnitude. Our results suggest that ecological engineers may enhance community diversity while increasing persistence by facilitating colonization and limiting competitive exclusion.
A yeast platform for high-level synthesis of tetrahydroisoquinoline alkaloids
Authors: Pyne Michael E. , Kevvai Kaspar , Grewal Parbir S. , Narcross Lauren , Choi Brian , Bourgeois Leanne , Dueber John E. , Martin Vincent J. J.
Published: July 2020

The tetrahydroisoquinoline (THIQ) moiety is a privileged substructure of many bioactive natural products and semi-synthetic analogs. Plants manufacture more than 3,000 THIQ alkaloids, including the opioids morphine and codeine. While microbial species have been engineered to synthesize a few compounds from the benzylisoquinoline alkaloid (BIA) family of THIQs, low product titers impede industrial viability and limit access to the full chemical space. Here we report a yeast THIQ platform by increasing production of the central BIA intermediate (S)-reticuline to 4.6 g L−1, a 57,000-fold improvement over our first-generation strain. We show that gains in BIA output coincide with the formation of several substituted THIQs derived from amino acid catabolism. We use these insights to repurpose the Ehrlich pathway and synthesize an array of THIQ structures. This work provides a blueprint for building diverse alkaloid scaffolds and enables the targeted overproduction of thousands of THIQ products, including natural and semi-synthetic opioids.
Manipulating interstitial carbon atoms in the nickel octahedral site for highly efficient hydrogenation of alkyne
Authors: Niu Yiming , Huang Xing , Wang Yongzhao , Xu Ming , Chen Junnan , Xu Shuliang , Willinger Marc-Georg , Zhang Wei , Wei Min , Zhang Bingsen
Published: July 2020

Light elements in the interstitial site of transition metals have strong influence on heterogeneous catalysis via either expression of surface structures or even direct participation into reaction. Interstitial atoms are generally metastable with a strong environmental dependence, setting up giant challenges in controlling of heterogeneous catalysis. Herein, we show that the desired carbon atoms can be manipulated within nickel (Ni) lattice for improving the selectivity in acetylene hydrogenation reaction. The radius of octahedral space of Ni is expanded from 0.517 to 0.524 Å via formation of Ni3Zn, affording the dissociated carbon atoms to readily dissolve and diffuse at mild temperatures. Such incorporated carbon atoms coordinate with the surrounding Ni atoms for generation of Ni3ZnC0.7 and thereof inhibit the formation of subsurface hydrogen structures. Thus, the selectivity and stability are dramatically improved, as it enables suppressing the pathway of ethylene hydrogenation and restraining the accumulation of carbonaceous species on surface.
Upgrading ketone synthesis direct from carboxylic acids and organohalides
Authors: Ruzi Rehanguli , Liu Kai , Zhu Chengjian , Xie Jin
Published: July 2020

The ketone functional group has a unique reactivity in organic chemistry and is associated with a number of useful reactions. Catalytic methods for ketone synthesis are continually being developed. Here, we report a photoredox, nickel and phosphoranyl radical synergistic cross-electrophile coupling of commercially available chemicals, aromatic acids and aryl/alkyl bromides. This allows for concise synthesis of highly functionalized ketones directly, without the preparation of activated carbonyl intermediates or organometallic compounds, and thus complements the conventional Weinreb ketone synthesis. Use of the appropriate photocatalyst, ligand amount and solvents can match the reaction rate required by any simple catalytic cycle. The practicality and synthetic robustness of the reaction are illustrated by the facile synthesis of complex ketones from readily available feedstock chemicals.
The microscopic origin of DMI in magnetic bilayers and prediction of giant DMI in new bilayers
Authors: Jadaun Priyamvada , Register Leonard F. , Banerjee Sanjay K.
Published: July 2020

Skyrmions are widely regarded as promising candidates for emergent spintronic devices. Dzyaloshinskii–Moriya interaction (DMI) is often critical to the generation and manipulation of skyrmions. However, there is a fundamental lack of understanding of the origin of DMI or the mechanism by which DMI generates skyrmions in magnetic bilayers. Very little is known of the material parameters that determine the value of DMI. This knowledge is vital for rational design of skyrmion materials and further development of skyrmion technology. To address this important problem, we investigate DMI in magnetic bilayers using first principles. We present a new theoretical model that explains the microscopic origin of DMI in magnetic bilayers. We demonstrate that DMI depends on two parameters, interfacial hybridization and orbital contributions of the heavy metal. Using these parameters, we explain the trend of DMI observed. We also report four new materials systems with giant DMI and new designs for magnetic multilayers that are expected to outperform the best materials known so far. Our results present a notably new understanding of DMI, uncover highly promising materials and put forth pathways for the controlled generation of skyrmions.
MARES, a replicable pipeline and curated reference database for marine eukaryote metabarcoding
Authors: Arranz Vanessa , Pearman William S. , Aguirre J. David , Liggins Libby
Published: July 2020

The use of DNA metabarcoding to characterise the biodiversity of environmental and community samples has exploded in recent years. However, taxonomic inferences from these studies are contingent on the quality and completeness of the sequence reference database used to characterise sample species-composition. In response, studies often develop custom reference databases to improve species assignment. The disadvantage of this approach is that it limits the potential for database re-use, and the transferability of inferences across studies. Here, we present the MARine Eukaryote Species (MARES) reference database for use in marine metabarcoding studies, created using a transparent and reproducible pipeline. MARES includes all COI sequences available in GenBank and BOLD for marine taxa, unified into a single taxonomy. Our pipeline facilitates the curation of sequences, synonymization of taxonomic identifiers used by different repositories, and formatting these data for use in taxonomic assignment tools. Overall, MARES provides a benchmark COI reference database for marine eukaryotes, and a standardised pipeline for (re)producing reference databases enabling integration and fair comparison of marine DNA metabarcoding results.
Local dispersal pathways during the invasion of the cactus moth, Cactoblastis cactorum, within North America and the Caribbean
Authors: Andraca-Gómez Guadalupe , Lombaert Eric , Ordano Mariano , Pérez-Ishiwara Rubén , Boege Karina , Domínguez César A. , Fornoni Juan
Published: July 2020

Cactoblastis cactorum, a species of moth native to Argentina, feeds on several prickly pear cactus species (Opuntia) and has been successfully used as a biological control of invading Opuntia species in Australia, South Africa and native ruderal Opuntia species in some Caribbean islands. Since its introduction to the Caribbean its spread was uncontrolled, invading successfully Florida, Texas and Louisiana. Despite this long history of invasion, we are still far from understanding the factors determining the patterns of invasion of Cactoblastis in North America. Here, we explored three non-mutually exclusive explanations: a) a stepping stone model of colonization, b) long distance colonization due to hurricanes, and/or c) hitchhiking through previously reported commercial routes. Genetic diversity, genetic structure and the patterns of migration among populations were obtained by analyzing 10 nuclear microsatellite loci. Results revealed the presence of genetic structure among populations of C. cactorum in the invaded region and suggest that both marine commercial trade between the Caribbean islands and continental USA, as well as recurrent transport by hurricanes, explain the observed patterns of colonization. Provided that sanitary regulations avoiding human-mediated dispersal are enforced, hurricanes probably represent the most important agent of dispersal and future invasion to continental areas.
Bubbles determine the amount of alcohol in Mezcal
Authors: Rage G. , Atasi O. , Wilhelmus M. M. , Hernández-Sánchez J. F. , Haut B. , Scheid B. , Legendre D. , Zenit R.
Published: July 2020

Mezcal is a traditional Mexican spirit, obtained from the distillation of fermented agave juices. Its preparation has been conducted for centuries in an artisanal manner. The method used to determine the correct alcohol content is of particular interest: a stream of the liquor is poured into a small vessel to induce surface bubbles. These bubbles, known as pearls by the Mezcal artisans, remain stable for tenths of seconds only if the alcohol content is close to 50%. For higher or lower alcohol content, the bubbles burst rapidly. The long bubble lifetime is the result of surfactant-induced surface tension changes. However, the precise mechanism and its relation to alcohol content remain unexplained. In this investigation, the extended lifetime of pearls was studied both experimentally and numerically. It was found that changes in surface tension, density, viscosity (resulting from mixing ethanol and water), and the presence of surfactants are all relevant to extend the bubble lifetime. The dimensionless bubble lifetime was found to reach its maximum value when the Bond number was close to unity, corresponding to 2 mm Mezcal bubbles. These findings show that the traditional empirical method does work. Beyond this, the understanding of the process provides physical insight to many other natural and industrial problems for which the stability of surface bubbles is of importance, such as bio-foams, froth floatation, and volcanic flows.
Impact of quantitative pulmonary emphysema score on the rate of pneumothorax and chest tube insertion in CT-guided lung biopsies
Authors: Theilig Dorothea , Petschelt David , Mayerhofer Anna , Hamm Bernd , Gebauer Bernhard , Geisel Dominik
Published: July 2020

The aim of this study was to evaluate the risk of pneumothorax and need for chest tube insertion in CT-guided lung biopsies and identify predictors focusing on pulmonary emphysema determined with quantitative computed tomography. To that end, we retrospectively analysed the incidence of pneumothorax and chest tube insertion in 371 CT-guided lung biopsies with respect to the quantitative emphysema score determined with the density mask technique. Other possible impact factors considered were lesion diameter, length of biopsy pathway within the lung parenchyma, lung lobe, needle size, puncture technique, patient positioning and interventionalist’s level of experience. Quantitative emphysema scores of the lung were significantly higher in patients who developed instant pneumothorax (27%, p < 0.0001), overall pneumothorax (38%, p = 0.001) and had chest tube insertion (9%, p = 0.006) compared to those who did not when analysed with the Mann–Whitney U-test. In logistic regression analysis with inclusion of the other possible impact factors, the quantitative emphysema score remained a statistically significant predictor for all three output parameters. This was confirmed with least absolute shrinkage and selection operator (Lasso) regression analysis. In conclusion, quantitatively determined pulmonary emphysema is a positive predictor of the pneumothorax rate in CT-guided lung biopsy and likelihood of chest tube insertion.
Investigations of an inducible intact dystrophin gene excision system in cardiac and skeletal muscle in vivo
Authors: Bez Batti Angulski Addeli , Bauer John , Cohen Houda , Kobuke Kazuhiro , Campbell Kevin P. , Metzger Joseph M.
Published: July 2020

We sought here to induce the excision of a large intragenic segment within the intact dystrophin gene locus, with the ultimate goal to elucidate dystrophin protein function and stability in striated muscles in vivo. To this end, we implemented an inducible-gene excision methodology using a floxed allele approach, demarcated by dystrophin exons 2–79, in complementation with a cardiac and skeletal muscle directed gene deletion system for spatial–temporal control of dystrophin gene excision in vivo. Main findings of this study include evidence of significant intact dystrophin gene excision, ranging from ~ 25% in heart muscle to ~ 30–35% in skeletal muscles in vivo. Results show that despite evidence of significant dystrophin gene excision, no significant decrease in dystrophin protein content was evident by Western blot analysis, at three months post excision in skeletal muscles or by 6 months post gene excision in heart muscle. Challenges of in vivo dystrophin gene excision revealed acute deleterious effects of tamoxifen on striated muscles, including a transient down regulation in dystrophin gene transcription in the absence of dystrophin gene excision. In addition, technical limitations of incomplete dystrophin gene excision became apparent that, in turn, tempered interpretation. Collectively, these findings are in keeping with earlier studies suggesting the dystrophin protein to be long-lived in striated muscles in vivo; however, more rigorous quantitative analysis of dystrophin stability in vivo will require future works in which more complete gene excision can be demonstrated, and without significant off-target effects of the gene deletion experimental platform per se.
Realistic simulation of virtual multi-scale, multi-modal patient trajectories using Bayesian networks and sparse auto-encoders
Authors: Sood Meemansa , Sahay Akrishta , Karki Reagon , Emon Mohammad Asif , Vrooman Henri , Hofmann-Apitius Martin , Fröhlich Holger
Published: July 2020

Translational research of many disease areas requires a longitudinal understanding of disease development and progression across all biologically relevant scales. Several corresponding studies are now available. However, to compile a comprehensive picture of a specific disease, multiple studies need to be analyzed and compared. A large number of clinical studies is nowadays conducted in the context of drug development in pharmaceutical research. However, legal and ethical constraints typically do not allow for sharing sensitive patient data. In consequence there exist data “silos”, which slow down the overall scientific progress in translational research. In this paper, we suggest the idea of a virtual cohort (VC) to address this limitation. Our key idea is to describe a longitudinal patient cohort with the help of a generative statistical model, namely a modular Bayesian Network, in which individual modules are represented as sparse autoencoder networks. We show that with the help of such a model we can simulate subjects that are highly similar to real ones. Our approach allows for incorporating arbitrary multi-scale, multi-modal data without making specific distribution assumptions. Moreover, we demonstrate the possibility to simulate interventions (e.g. via a treatment) in the VC. Overall, our proposed approach opens the possibility to build sufficiently realistic VCs for multiple disease areas in the future.
Prediction accuracy of L- and M-cone based human pupil light models
Authors: Zandi Babak , Klabes Julian , Khanh Tran Quoc
Published: July 2020

Multi-channel LED luminaires offer a powerful tool to vary retinal receptor signals while keeping visual parameters such as color or brightness perception constant. This technology could provide new fields of application in indoor lighting since the spectrum can be enhanced individually to the users’ favor or task. One possible application would be to optimize a light spectrum by using the pupil diameter as a parameter to increase the visual acuity. A spectral- and time-dependent pupil model is the key requirement for this aim. We benchmarked in our work selected L- and M-cone based pupil models to find the estimation error in predicting the pupil diameter for chromatic and polychromatic spectra at 100 cd/m2. We report an increased estimation error up to 1.21 mm for 450 nm at 60–300 s exposure time. At short exposure times, the pupil diameter was approximately independent of the used spectrum, allowing to use the luminance for a pupil model. Polychromatic spectra along the Planckian locus showed at 60–300 s exposure time, a prediction error within a tolerance range of ± 0.5 mm. The time dependency seems to be more essential than the spectral dependency when using polychromatic spectra.
Diagnosis of cytomegalovirus infection from clinical whole genome sequencing
Authors: Ramchandar Nanda , Ding Yan , Farnaes Lauge , Dimmock David , Hobbs Charlotte , Kingsmore Stephen F. , Bainbridge Matthew
Published: July 2020

Rapid whole genome sequencing (rWGS) of peripheral blood has been used to detect microbial DNA in acute infections. Cytomegalovirus (CMV) is a herpesvirus capable of causing severe disease in neonates and immunocompromised patients. We identified CMV in patients undergoing diagnostic rWGS by matching reads that did not align to the human reference genome to a database of microbial genomes. rWGS was conducted on peripheral blood obtained from ill pediatric patients (age 1 day to 18 years). Reads not aligning to the human genome were analyzed using an in-house pipeline to identify DNA consistent with CMV infection. Of 669 patients who received rWGS from July 2016 through July 2019, we identified 28 patients (4.2%) with reads that aligned to the CMV reference genome. Six of these patients had clinical findings consistent with symptomatic CMV infection. Positive results were highly correlated (R2 > 0.99, p < 0.001) to a CMV-qPCR assay conducted on DNA isolated from whole blood samples. In acutely ill children receiving rWGS for diagnosis of genetic disease, we propose analysis of patient genetic data to identify CMV, which could impact treatment of up to 4% of children in the intensive care unit.
Data-derived metrics describing the behaviour of field-based citizen scientists provide insights for project design and modelling bias
Authors: August Tom , Fox Richard , Roy David B. , Pocock Michael J. O.
Published: July 2020

Around the world volunteers and non-professionals collect data as part of environmental citizen science projects, collecting wildlife observations, measures of water quality and much more. However, where projects allow flexibility in how, where, and when data are collected there will be variation in the behaviour of participants which results in biases in the datasets collected. We develop a method to quantify this behavioural variation, describing the key drivers and providing a tool to account for biases in models that use these data. We used a suite of metrics to describe the temporal and spatial behaviour of participants, as well as variation in the data they collected. These were applied to 5,268 users of the iRecord Butterflies mobile phone app, a multi-species environmental citizen science project. In contrast to previous studies, after removing transient participants (those active on few days and who contribute few records), we do not find evidence of clustering of participants; instead, participants fall along four continuous axes that describe variation in participants’ behaviour: recording intensity, spatial extent, recording potential and rarity recording. Our results support a move away from labelling participants as belonging to one behavioural group or another in favour of placing them along axes of participant behaviour that better represent the continuous variation between individuals. Understanding participant behaviour could support better use of the data, by accounting for biases in the data collection process.
Noninvasive and safe cell viability assay for Paramecium using natural pigment extracted from food
Authors: Yamashita Kyohei , Tokunaga Eiji
Published: July 2020

Noninvasive, safe and cost-effective cell viability assay is important in many fields of biological research such as cell culture and counting. We examined ten typical natural pigments extracted from food to find that Monascus pigment (MP) or anthocyanin pigment (AP: purple sweet potato and purple cabbage) with Tris (Trimethylolaminomethane) works as a good indicator of viability assay for dye exclusion test (DET) of Paramecium. This was confirmed spectrally by scan-free, non-invasive absorbance spectral imaging A (x, y, λ) microscopy. We developed a new method of cell capture using a metal mesh to confine live Paramecium in a restricted space. This has the advantage that a low-cost and robust capture can be fabricated without using special equipment, compared to a conventional lab-on-a-chip. As a result, MP and AP stained dead cells as quick as methylene blue (MB), a synthetic dye conventionally used in DET within 1 min when treated with microwave and benzalkonium chloride. The natural pigments with Tris had little effect on inhibiting the growth of Paramecium, but MB killed all the cells within 1 h. MP is most useful because it allows non-invasive DET without Tris. This approach provides less invasive and safe DET.