bluuebunny/crossref_metadata_2025 huggingface dataset:
Segmented flow generator for serial crystallography at the European X-ray free electron laser
Authors: Echelmeier Austin , Cruz Villarreal Jorvani , Messerschmidt Marc , Kim Daihyun , Coe Jesse D. , Thifault Darren , Botha Sabine , Egatz-Gomez Ana , Gandhi Sahir , Brehm Gerrit , Conrad Chelsie E. , Hansen Debra T. , Madsen Caleb , Bajt Saša , Meza-Aguilar J. Domingo , Oberthür Dominik , Wiedorn Max O. , Fleckenstein Holger , Mendez Derek , Knoška Juraj , Martin-Garcia Jose M. , Hu Hao , Lisova Stella , Allahgholi Aschkan , Gevorkov Yaroslav , Ayyer Kartik , Aplin Steve , Ginn Helen Mary , Graafsma Heinz , Morgan Andrew J. , Greiffenberg Dominic , Klujev Alexander , Laurus Torsten , Poehlsen Jennifer , Trunk Ulrich , Mezza Davide , Schmidt Bernd , Kuhn Manuela , Fromme Raimund , Sztuk-Dambietz Jolanta , Raab Natascha , Hauf Steffen , Silenzi Alessandro , Michelat Thomas , Xu Chen , Danilevski Cyril , Parenti Andrea , Mekinda Leonce , Weinhausen Britta , Mills Grant , Vagovic Patrik , Kim Yoonhee , Kirkwood Henry , Bean Richard , Bielecki Johan , Stern Stephan , Giewekemeyer Klaus , Round Adam R. , Schulz Joachim , Dörner Katerina , Grant Thomas D. , Mariani Valerio , Barty Anton , Mancuso Adrian P. , Weierstall Uwe , Spence John C. H. , Chapman Henry N. , Zatsepin Nadia , Fromme Petra , Kirian Richard A. , Ros Alexandra
Published: September 2020

Serial femtosecond crystallography (SFX) with X-ray free electron lasers (XFELs) allows structure determination of membrane proteins and time-resolved crystallography. Common liquid sample delivery continuously jets the protein crystal suspension into the path of the XFEL, wasting a vast amount of sample due to the pulsed nature of all current XFEL sources. The European XFEL (EuXFEL) delivers femtosecond (fs) X-ray pulses in trains spaced 100 ms apart whereas pulses within trains are currently separated by 889 ns. Therefore, continuous sample delivery via fast jets wastes >99% of sample. Here, we introduce a microfluidic device delivering crystal laden droplets segmented with an immiscible oil reducing sample waste and demonstrate droplet injection at the EuXFEL compatible with high pressure liquid delivery of an SFX experiment. While achieving ~60% reduction in sample waste, we determine the structure of the enzyme 3-deoxy-D-manno-octulosonate-8-phosphate synthase from microcrystals delivered in droplets revealing distinct structural features not previously reported.
Identification of molecular quantum states using phase-sensitive forces
Authors: Najafian Kaveh , Meir Ziv , Sinhal Mudit , Willitsch Stefan
Published: September 2020

Quantum-logic techniques used to manipulate quantum systems are now increasingly being applied to molecules. Previous experiments on single trapped diatomic species have enabled state detection with excellent fidelities and highly precise spectroscopic measurements. However, for complex molecules with a dense energy-level structure improved methods are necessary. Here, we demonstrate an enhanced quantum protocol for molecular state detection using state-dependent forces. Our approach is based on interfering a reference and a signal force applied to a single atomic and molecular ion. By changing the relative phase of the forces, we identify states embedded in a dense molecular energy-level structure and monitor state-to-state inelastic scattering processes. This method can also be used to exclude a large number of states in a single measurement when the initial state preparation is imperfect and information on the molecular properties is incomplete. While the present experiments focus on N$${}_{2}^{+}$$

2

+

, the method is general and is expected to be of particular benefit for polyatomic systems.
CMTM6 expressed on the adaxonal Schwann cell surface restricts axonal diameters in peripheral nerves
Authors: Eichel Maria A. , Gargareta Vasiliki-Ilya , D’Este Elisa , Fledrich Robert , Kungl Theresa , Buscham Tobias J. , Lüders Katja A. , Miracle Cristina , Jung Ramona B. , Distler Ute , Kusch Kathrin , Möbius Wiebke , Hülsmann Swen , Tenzer Stefan , Nave Klaus-Armin , Werner Hauke B.
Published: September 2020

The velocity of nerve conduction is moderately enhanced by larger axonal diameters and potently sped up by myelination of axons. Myelination thus allows rapid impulse propagation with reduced axonal diameters; however, no myelin-dependent mechanism has been reported that restricts radial growth of axons. By label-free proteomics, STED-microscopy and cryo-immuno electron-microscopy we here identify CMTM6 (chemokine-like factor-like MARVEL-transmembrane domain-containing family member-6) as a myelin protein specifically localized to the Schwann cell membrane exposed to the axon. We find that disruption of Cmtm6-expression in Schwann cells causes a substantial increase of axonal diameters but does not impair myelin biogenesis, radial sorting or integrity of axons. Increased axonal diameters correlate with accelerated sensory nerve conduction and sensory responses and perturbed motor performance. These data show that Schwann cells utilize CMTM6 to restrict the radial growth of axons, which optimizes nerve function.
Single-cell transcriptomes of pancreatic preinvasive lesions and cancer reveal acinar metaplastic cells’ heterogeneity
Authors: Schlesinger Yehuda , Yosefov-Levi Oshri , Kolodkin-Gal Dror , Granit Roy Zvi , Peters Luriano , Kalifa Rachel , Xia Lei , Nasereddin Abdelmajeed , Shiff Idit , Amran Osher , Nevo Yuval , Elgavish Sharona , Atlan Karine , Zamir Gideon , Parnas Oren
Published: September 2020

Acinar metaplasia is an initial step in a series of events that can lead to pancreatic cancer. Here we perform single-cell RNA-sequencing of mouse pancreas during the progression from preinvasive stages to tumor formation. Using a reporter gene, we identify metaplastic cells that originated from acinar cells and express two transcription factors, Onecut2 and Foxq1. Further analyses of metaplastic acinar cell heterogeneity define six acinar metaplastic cell types and states, including stomach-specific cell types. Localization of metaplastic cell types and mixture of different metaplastic cell types in the same pre-malignant lesion is shown. Finally, single-cell transcriptome analyses of tumor-associated stromal, immune, endothelial and fibroblast cells identify signals that may support tumor development, as well as the recruitment and education of immune cells. Our findings are consistent with the early, premalignant formation of an immunosuppressive environment mediated by interactions between acinar metaplastic cells and other cells in the microenvironment.
A gas-to-particle conversion mechanism helps to explain atmospheric particle formation through clustering of iodine oxides
Authors: Gómez Martín Juan Carlos , Lewis Thomas R. , Blitz Mark A. , Plane John M. C. , Kumar Manoj , Francisco Joseph S. , Saiz-Lopez Alfonso
Published: September 2020

Emitted from the oceans, iodine-bearing molecules are ubiquitous in the atmosphere and a source of new atmospheric aerosol particles of potentially global significance. However, its inclusion in atmospheric models is hindered by a lack of understanding of the first steps of the photochemical gas-to-particle conversion mechanism. Our laboratory results show that under a high humidity and low HOx regime, the recently proposed nucleating molecule (iodic acid, HOIO2) does not form rapidly enough, and gas-to-particle conversion proceeds by clustering of iodine oxides (IxOy), albeit at slower rates than under dryer conditions. Moreover, we show experimentally that gas-phase HOIO2 is not necessary for the formation of HOIO2-containing particles. These insights help to explain new particle formation in the relatively dry polar regions and, more generally, provide for the first time a thermochemically feasible molecular mechanism from ocean iodine emissions to atmospheric particles that is currently missing in model calculations of aerosol radiative forcing.
DNA methylation study of Huntington’s disease and motor progression in patients and in animal models
Authors: Lu Ake T. , Narayan Pritika , Grant Matthew J. , Langfelder Peter , Wang Nan , Kwak Seung , Wilkinson Hilary , Chen Richard Z. , Chen Jian , Simon Bawden C. , Rudiger Skye R. , Ciosi Marc , Chatzi Afroditi , Maxwell Alastair , Hore Timothy A. , Aaronson Jeff , Rosinski Jim , Preiss Alicia , Vogt Thomas F. , Coppola Giovanni , Monckton Darren , Snell Russell G. , William Yang X. , Horvath Steve
Published: September 2020

Although Huntington’s disease (HD) is a well studied Mendelian genetic disorder, less is known about its associated epigenetic changes. Here, we characterize DNA methylation levels in six different tissues from 3 species: a mouse huntingtin (Htt) gene knock-in model, a transgenic HTT sheep model, and humans. Our epigenome-wide association study (EWAS) of human blood reveals that HD mutation status is significantly (p < 10−7) associated with 33 CpG sites, including the HTT gene (p = 6.5 × 10−26). These Htt/HTT associations were replicated in the Q175 Htt knock-in mouse model (p = 6.0 × 10−8) and in the transgenic sheep model (p = 2.4 × 10−88). We define a measure of HD motor score progression among manifest HD cases based on multiple clinical assessments. EWAS of motor progression in manifest HD cases exhibits significant (p < 10−7) associations with methylation levels at three loci: near PEX14 (p = 9.3 × 10−9), GRIK4 (p = 3.0 × 10−8), and COX4I2 (p = 6.5 × 10−8). We conclude that HD is accompanied by profound changes of DNA methylation levels in three mammalian species.
Exhausted CD8+ T cells exhibit low and strongly inhibited TCR signaling during chronic LCMV infection
Authors: Sandu Ioana , Cerletti Dario , Claassen Manfred , Oxenius Annette
Published: September 2020

Chronic viral infections are often associated with impaired CD8+ T cell function, referred to as exhaustion. Although the molecular and cellular circuits involved in CD8+ T cell exhaustion are well defined, with sustained presence of antigen being one important parameter, how much T cell receptor (TCR) signaling is actually ongoing in vivo during established chronic infection is unclear. Here, we characterize the in vivo TCR signaling of virus-specific exhausted CD8+ T cells in a mouse model, leveraging TCR signaling reporter mice in combination with transcriptomics. In vivo signaling in exhausted cells is low, in contrast to their in vitro signaling potential, and despite antigen being abundantly present. Both checkpoint blockade and adoptive transfer of naïve target cells increase TCR signaling, demonstrating that engagement of co-inhibitory receptors curtails CD8+ T cell signaling and function in vivo.
Mantle flow distribution beneath the California margin
Authors: Barbot Sylvain
Published: September 2020

Although the surface deformation of tectonic plate boundaries is well determined by geological and geodetic measurements, the pattern of flow below the lithosphere remains poorly constrained. We use the crustal velocity field of the Plate Boundary Observatory to illuminate the distribution of horizontal flow beneath the California margin. At lower-crustal and upper-mantle depths, the boundary between the Pacific and North American plates is off-centered from the San Andreas fault, concentrated in a region that encompasses the trace of nearby active faults. A major step is associated with return flow below the Eastern California Shear Zone, leading to the extrusion of the Mojave block and a re-distribution of fault activity since the Pleistocene. Major earthquakes in California have occurred above the regions of current plastic strain accumulation. Deformation is mechanically coupled from the crust to the asthenosphere, with mantle flow overlaid by a kinematically consistent network of faults in the brittle crust.
Functional regulation of an ancestral RAG transposon ProtoRAG by a trans-acting factor YY1 in lancelet
Authors: Liu Song , Yuan Shaochun , Gao Xiaoman , Tao Xin , Yu Wenjuan , Li Xu , Chen Shangwu , Xu Anlong
Published: September 2020

The discovery of ancestral RAG transposons in early deuterostomia reveals the origin of vertebrate V(D)J recombination. Here, we analyze the functional regulation of a RAG transposon, ProtoRAG, in lancelet. We find that a specific interaction between the cis-acting element within the TIR sequences of ProtoRAG and a trans-acting factor, lancelet YY1-like (bbYY1), is important for the transcriptional regulation of lancelet RAG-like genes (bbRAG1L and bbRAG2L). Mechanistically, bbYY1 suppresses the transposition of ProtoRAG; meanwhile, bbYY1 promotes host DNA rejoins (HDJ) and TIR-TIR joints (TTJ) after TIR-dependent excision by facilitating the binding of bbRAG1L/2 L to TIR-containing DNA, and by interacting with the bbRAG1L/2 L complex. Our data thus suggest that bbYY1 has dual functions in fine-tuning the activity of ProtoRAG and maintaining the genome stability of the host.
Graphdiyne-modified TiO2 nanofibers with osteoinductive and enhanced photocatalytic antibacterial activities to prevent implant infection
Authors: Wang Rui , Shi Miusi , Xu Feiyan , Qiu Yun , Zhang Peng , Shen Kailun , Zhao Qin , Yu Jiaguo , Zhang Yufeng
Published: September 2020

Titanium implants have been widely used in bone tissue engineering for decades. However, orthopedic implant-associated infections increase the risk of implant failure and even lead to amputation in severe cases. Although TiO2has photocatalytic activity to produce reactive oxygen species (ROS), the recombination of generated electrons and holes limits its antibacterial ability. Here, we describe a graphdiyne (GDY) composite TiO2nanofiber that combats implant infections through enhanced photocatalysis and prolonged antibacterial ability. In addition, GDY-modified TiO2nanofibers exert superior biocompatibility and osteoinductive abilities for cell adhesion and differentiation, thus contributing to the bone tissue regeneration process in drug-resistant bacteria-induced implant infection.
Converting microwave and telecom photons with a silicon photonic nanomechanical interface
Authors: Arnold G. , Wulf M. , Barzanjeh S. , Redchenko E. S. , Rueda A. , Hease W. J. , Hassani F. , Fink J. M.
Published: September 2020

Practical quantum networks require low-loss and noise-resilient optical interconnects as well as non-Gaussian resources for entanglement distillation and distributed quantum computation. The latter could be provided by superconducting circuits but existing solutions to interface the microwave and optical domains lack either scalability or efficiency, and in most cases the conversion noise is not known. In this work we utilize the unique opportunities of silicon photonics, cavity optomechanics and superconducting circuits to demonstrate a fully integrated, coherent transducer interfacing the microwave X and the telecom S bands with a total (internal) bidirectional transduction efficiency of 1.2% (135%) at millikelvin temperatures. The coupling relies solely on the radiation pressure interaction mediated by the femtometer-scale motion of two silicon nanobeams reaching a Vπ as low as 16 μV for sub-nanowatt pump powers. Without the associated optomechanical gain, we achieve a total (internal) pure conversion efficiency of up to 0.019% (1.6%), relevant for future noise-free operation on this qubit-compatible platform.
Substantial underestimation of SARS-CoV-2 infection in the United States
Authors: Wu Sean L. , Mertens Andrew N. , Crider Yoshika S. , Nguyen Anna , Pokpongkiat Nolan N. , Djajadi Stephanie , Seth Anmol , Hsiang Michelle S. , Colford John M. , Reingold Art , Arnold Benjamin F. , Hubbard Alan , Benjamin-Chung Jade
Published: September 2020

Accurate estimates of the burden of SARS-CoV-2 infection are critical to informing pandemic response. Confirmed COVID-19 case counts in the U.S. do not capture the total burden of the pandemic because testing has been primarily restricted to individuals with moderate to severe symptoms due to limited test availability. Here, we use a semi-Bayesian probabilistic bias analysis to account for incomplete testing and imperfect diagnostic accuracy. We estimate 6,454,951 cumulative infections compared to 721,245 confirmed cases (1.9% vs. 0.2% of the population) in the United States as of April 18, 2020. Accounting for uncertainty, the number of infections during this period was 3 to 20 times higher than the number of confirmed cases. 86% (simulation interval: 64–99%) of this difference is due to incomplete testing, while 14% (0.3–36%) is due to imperfect test accuracy. The approach can readily be applied in future studies in other locations or at finer spatial scale to correct for biased testing and imperfect diagnostic accuracy to provide a more realistic assessment of COVID-19 burden.
Photo-mediated selective deconstructive geminal dihalogenation of trisubstituted alkenes
Authors: Wang Han , Toh Ren Wei , Shi Xiangcheng , Wang Tonglin , Cong Xu , Wu Jie
Published: September 2020

Selective deconstructive functionalization of alkenes, other than the well-established olefin metathesis and ozonolysis, to produce densely functionalized molecular scaffolds is highly attractive but challenging. Here we report an efficient photo-mediated deconstructive germinal dihalogenation of carbon-carbon double bonds. A wide range of geminal diiodoalkanes and bromo(iodo)alkanes (>40 examples) are directly prepared from various trisubstituted alkenes, including both cyclic and acyclic olefins. This C=C cleavage is highly chemoselective and produces geminal dihalide ketones in good yields. Mechanistic investigations suggest a formation of alkyl hypoiodites from benzyl alcohols and N-iodoimides, which undergo light-induced homolytic cleavage to generate active oxygen radical species.
A distinct lineage of Caudovirales that encodes a deeply branching multi-subunit RNA polymerase
Authors: Weinheimer Alaina R. , Aylward Frank O.
Published: September 2020

Bacteriophages play critical roles in the biosphere, but their vast genomic diversity has obscured their evolutionary origins, and phylogenetic analyses have traditionally been hindered by their lack of universal phylogenetic marker genes. In this study we mine metagenomic data and identify a clade of Caudovirales that encodes the β and β′ subunits of multi-subunit RNA polymerase (RNAP), a high-resolution phylogenetic marker which enables detailed evolutionary analyses. Our RNAP phylogeny revealed that the Caudovirales RNAP forms a clade distinct from cellular homologs, suggesting an ancient acquisition of this enzyme. Within these multimeric RNAP-encoding Caudovirales (mReC), we find that the similarity of major capsid proteins and terminase large subunits further suggests they form a distinct clade with common evolutionary origin. Our study characterizes a clade of RNAP-encoding Caudovirales and suggests the ancient origin of this enzyme in this group, underscoring the important role of viruses in the early evolution of life on Earth.
Real-time monitoring of single ZTP riboswitches reveals a complex and kinetically controlled decision landscape
Authors: Hua Boyang , Jones Christopher P. , Mitra Jaba , Murray Peter J. , Rosenthal Rebecca , Ferré-D’Amaré Adrian R. , Ha Taekjip
Published: September 2020

RNAs begin to fold and function during transcription. Riboswitches undergo cotranscriptional switching in the context of transcription elongation, RNA folding, and ligand binding. To investigate how these processes jointly modulate the function of the folate stress-sensing Fusobacterium ulcerans ZTP riboswitch, we apply a single-molecule vectorial folding (VF) assay in which an engineered superhelicase Rep-X sequentially releases fluorescently labeled riboswitch RNA from a heteroduplex in a 5′-to-3′ direction, at ~60 nt s−1 [comparable to the speed of bacterial RNA polymerase (RNAP)]. We demonstrate that the ZTP riboswitch is kinetically controlled and that its activation is favored by slower unwinding, strategic pausing between but not before key folding elements, or a weakened transcription terminator. Real-time single-molecule monitoring captures folding riboswitches in multiple states, including an intermediate responsible for delayed terminator formation. These results show how individual nascent RNAs occupy distinct channels within the folding landscape that controls the fate of the riboswitch.
Re-imagining fMRI for awake behaving infants
Authors: Ellis C. T. , Skalaban L. J. , Yates T. S. , Bejjanki V. R. , Córdova N. I. , Turk-Browne N. B.
Published: September 2020

Thousands of functional magnetic resonance imaging (fMRI) studies have provided important insight into the human brain. However, only a handful of these studies tested infants while they were awake, because of the significant and unique methodological challenges involved. We report our efforts to address these challenges, with the goal of creating methods for awake infant fMRI that can reveal the inner workings of the developing, preverbal mind. We use these methods to collect and analyze two fMRI datasets obtained from infants during cognitive tasks, released publicly with this paper. In these datasets, we explore and evaluate data quantity and quality, task-evoked activity, and preprocessing decisions. We disseminate these methods by sharing two software packages that integrate infant-friendly cognitive tasks and eye-gaze monitoring with fMRI acquisition and analysis. These resources make fMRI a feasible and accessible technique for cognitive neuroscience in awake and behaving human infants.
Transgenerational inheritance of impaired larval T cell development in zebrafish
Authors: Iwanami Norimasa , Lawir Divine-Fondzenyuy , Sikora Katarzyna , O´Meara Connor , Takeshita Kohei , Schorpp Michael , Boehm Thomas
Published: September 2020

Evidence for transgenerational inheritance of epigenetic information in vertebrates is scarce. Aberrant patterns of DNA methylation in gametes may set the stage for transmission into future generations. Here, we describe a viable hypomorphic allele of dnmt1 in zebrafish that causes widespread demethylation of CpG dinucleotides in sperm and somatic tissues. We find that homozygous mutants are essentially normal, with the exception of drastically impaired lymphopoiesis, affecting both larval and adult phases of T cell development. The phenotype of impaired larval (but not adult) T cell development is transmitted to subsequent generations by genotypically wildtype fish. We further find that about 200 differentially methylated regions in sperm DNA of transmitting and non-transmitting males, including hypermethylated sites associated with runx3 and rptor genes, whose reduced activities are associated with impaired larval T cell development. Our results indicate a particular sensitivity of larval T cell development to transgenerationally inherited epimutations.
Wrapping glia regulates neuronal signaling speed and precision in the peripheral nervous system of Drosophila
Authors: Kottmeier Rita , Bittern Jonas , Schoofs Andreas , Scheiwe Frederieke , Matzat Till , Pankratz Michael , Klämbt Christian
Published: September 2020

The functionality of the nervous system requires transmission of information along axons with high speed and precision. Conductance velocity depends on axonal diameter whereas signaling precision requires a block of electrical crosstalk between axons, known as ephaptic coupling. Here, we use the peripheral nervous system of Drosophila larvae to determine how glia regulates axonal properties. We show that wrapping glial differentiation depends on gap junctions and FGF-signaling. Abnormal glial differentiation affects axonal diameter and conductance velocity and causes mild behavioral phenotypes that can be rescued by a sphingosine-rich diet. Ablation of wrapping glia does not further impair axonal diameter and conductance velocity but causes a prominent locomotion phenotype that cannot be rescued by sphingosine. Moreover, optogenetically evoked locomotor patterns do not depend on conductance speed but require the presence of wrapping glial processes. In conclusion, our data indicate that wrapping glia modulates both speed and precision of neuronal signaling.
Swelling-strengthening hydrogels by embedding with deformable nanobarriers
Authors: Wu Feng , Pang Yan , Liu Jinyao
Published: September 2020

Biological tissues, such as muscle, can increase their mechanical strength after swelling due to the existence of many biological membrane barriers that can regulate the transmembrane transport of water molecules and ions. Oppositely, typical synthetic materials show a swelling-weakening behavior, which always suffers from a sharp decline in mechanical strength after swelling, because of the dilution of the network. Here, we describe a swelling-strengthening phenomenon of polymer materials achieved by a bioinspired strategy. Liposomal membrane nanobarriers are covalently embedded in a crosslinked network to regulate transmembrane transport. After swelling, the stretched network deforms the liposomes and subsequently initiates the transmembrane diffusion of the encapsulated molecules that can trigger the formation of a new network from the preloaded precursor. Thanks to the tough nature of the double-network structure, the swelling-strengthening phenomenon is achieved to polymer hydrogels successfully. Swelling-triggered self-strengthening enables the development of various dynamic materials.
Scaling behavior of the quantum phase transition from a quantum-anomalous-Hall insulator to an axion insulator
Authors: Wu Xinyu , Xiao Di , Chen Chui-Zhen , Sun Jian , Zhang Ling , Chan Moses H. W. , Samarth Nitin , Xie X. C. , Lin Xi , Chang Cui-Zu
Published: September 2020

The phase transitions from one plateau to the next plateau or to an insulator in quantum Hall and quantum anomalous Hall (QAH) systems have revealed universal scaling behaviors. A magnetic-field-driven quantum phase transition from a QAH insulator to an axion insulator was recently demonstrated in magnetic topological insulator sandwich samples. Here, we show that the temperature dependence of the derivative of the longitudinal resistance on magnetic field at the transition point follows a characteristic power-law that indicates a universal scaling behavior for the QAH to axion insulator phase transition. Similar to the quantum Hall plateau to plateau transition, the QAH to axion insulator transition can also be understood by the Chalker–Coddington network model. We extract a critical exponent κ ~ 0.38 ± 0.02 in agreement with recent high-precision numerical results on the correlation length exponent of the Chalker–Coddington model at ν ~ 2.6, rather than the generally-accepted value of 2.33.
Androgen receptor signalling in macrophages promotes TREM-1-mediated prostate cancer cell line migration and invasion
Authors: Cioni Bianca , Zaalberg Anniek , van Beijnum Judy R. , Melis Monique H. M. , van Burgsteden Johan , Muraro Mauro J. , Hooijberg Erik , Peters Dennis , Hofland Ingrid , Lubeck Yoni , de Jong Jeroen , Sanders Joyce , Vivié Judith , van der Poel Henk G. , de Boer Jan Paul , Griffioen Arjan W. , Zwart Wilbert , Bergman Andries M.
Published: September 2020

The androgen receptor (AR) is the master regulator of prostate cancer (PCa) development, and inhibition of AR signalling is the most effective PCa treatment. AR is expressed in PCa cells and also in the PCa-associated stroma, including infiltrating macrophages. Macrophages have a decisive function in PCa initiation and progression, but the role of AR in macrophages remains largely unexplored. Here, we show that AR signalling in the macrophage-like THP-1 cell line supports PCa cell line migration and invasion in culture via increased Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) signalling and expression of its downstream cytokines. Moreover, AR signalling in THP-1 and monocyte-derived macrophages upregulates IL-10 and markers of tissue residency. In conclusion, our data suggest that AR signalling in macrophages may support PCa invasiveness, and blocking this process may constitute one mechanism of anti-androgen therapy.
Global patterns of the leaf economics spectrum in wetlands
Authors: Pan Yingji , Cieraad Ellen , Armstrong Jean , Armstrong William , Clarkson Beverley R. , Colmer Timothy D. , Pedersen Ole , Visser Eric J. W. , Voesenek Laurentius A. C. J. , van Bodegom Peter M.
Published: September 2020

The leaf economics spectrum (LES) describes consistent correlations among a variety of leaf traits that reflect a gradient from conservative to acquisitive plant strategies. So far, whether the LES holds in wetland plants at a global scale has been unclear. Using data on 365 wetland species from 151 studies, we find that wetland plants in general show a shift within trait space along the same common slope as observed in non-wetland plants, with lower leaf mass per area, higher leaf nitrogen and phosphorus, faster photosynthetic rates, and shorter leaf life span compared to non-wetland plants. We conclude that wetland plants tend to cluster at the acquisitive end of the LES. The presented global quantifications of the LES in wetland plants enhance our understanding of wetland plant strategies in terms of resources acquisition and allocation, and provide a stepping-stone to developing trait-based approaches for wetland ecology.
Humanized single domain antibodies neutralize SARS-CoV-2 by targeting the spike receptor binding domain
Authors: Chi Xiaojing , Liu Xiuying , Wang Conghui , Zhang Xinhui , Li Xiang , Hou Jianhua , Ren Lili , Jin Qi , Wang Jianwei , Yang Wei
Published: September 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spreads worldwide and leads to an unprecedented medical burden and lives lost. Neutralizing antibodies provide efficient blockade for viral infection and are a promising category of biological therapies. Here, using SARS-CoV-2 spike receptor-binding domain (RBD) as a bait, we generate a panel of humanized single domain antibodies (sdAbs) from a synthetic library. These sdAbs reveal binding kinetics with the equilibrium dissociation constant (KD) of 0.99–35.5 nM. The monomeric sdAbs show half maximal neutralization concentration (EC50) of 0.0009–0.07 µg/mL and 0.13–0.51 µg/mL against SARS-CoV-2 pseudotypes, and authentic SARS-CoV-2, respectively. Competitive ligand-binding experiments suggest that the sdAbs either completely block or significantly inhibit the association between SARS-CoV-2 RBD and viral entry receptor ACE2. Fusion of the human IgG1 Fc to sdAbs improve their neutralization activity by up to ten times. These results support neutralizing sdAbs as a potential alternative for antiviral therapies.
Author Correction: mTORC2-AKT signaling to ATP-citrate lyase drives brown adipogenesis and de novo lipogenesis
Authors: Calejman C. Martinez , Trefely S. , Entwisle S. W. , Luciano A. , Jung S. M. , Hsiao W. , Torres A. , Hung C. M. , Li H. , Snyder N. W. , Villén J. , Wellen K. E. , Guertin D. A.
Published: September 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Guidelines for clinical trial protocols for interventions involving artificial intelligence: the SPIRIT-AI extension
Authors: Cruz Rivera Samantha , Liu Xiaoxuan , Chan An-Wen , Denniston Alastair K. , Calvert Melanie J. ,   The SPIRIT-AI and CONSORT-AI Working Group,   SPIRIT-AI and CONSORT-AI Steering Group, Darzi Ara , Holmes Christopher , Yau Christopher , Moher David , Ashrafian Hutan , Deeks Jonathan J. , Ferrante di Ruffano Lavinia , Faes Livia , Keane Pearse A. , Vollmer Sebastian J. ,   SPIRIT-AI and CONSORT-AI Consensus Group, Lee Aaron Y. , Jonas Adrian , Esteva Andre , Beam Andrew L. , Panico Maria Beatrice , Lee Cecilia S. , Haug Charlotte , Kelly Christophe J. , Yau Christopher , Mulrow Cynthia , Espinoza Cyrus , Fletcher John , Moher David , Paltoo Dina , Manna Elaine , Price Gary , Collins Gary S. , Harvey Hugh , Matcham James , Monteiro Joao , ElZarrad M. Khair , Ferrante di Ruffano Lavinia , Oakden-Rayner Luke , McCradden Melissa , Keane Pearse A. , Savage Richard , Golub Robert , Sarkar Rupa , Rowley Samuel
Published: September 2020

The SPIRIT 2013 statement aims to improve the completeness of clinical trial protocol reporting by providing evidence-based recommendations for the minimum set of items to be addressed. This guidance has been instrumental in promoting transparent evaluation of new interventions. More recently, there has been a growing recognition that interventions involving artificial intelligence (AI) need to undergo rigorous, prospective evaluation to demonstrate their impact on health outcomes. The SPIRIT-AI (Standard Protocol Items: Recommendations for Interventional Trials–Artificial Intelligence) extension is a new reporting guideline for clinical trial protocols evaluating interventions with an AI component. It was developed in parallel with its companion statement for trial reports: CONSORT-AI (Consolidated Standards of Reporting Trials–Artificial Intelligence). Both guidelines were developed through a staged consensus process involving literature review and expert consultation to generate 26 candidate items, which were consulted upon by an international multi-stakeholder group in a two-stage Delphi survey (103 stakeholders), agreed upon in a consensus meeting (31 stakeholders) and refined through a checklist pilot (34 participants). The SPIRIT-AI extension includes 15 new items that were considered sufficiently important for clinical trial protocols of AI interventions. These new items should be routinely reported in addition to the core SPIRIT 2013 items. SPIRIT-AI recommends that investigators provide clear descriptions of the AI intervention, including instructions and skills required for use, the setting in which the AI intervention will be integrated, considerations for the handling of input and output data, the human–AI interaction and analysis of error cases. SPIRIT-AI will help promote transparency and completeness for clinical trial protocols for AI interventions. Its use will assist editors and peer reviewers, as well as the general readership, to understand, interpret and critically appraise the design and risk of bias for a planned clinical trial.
Dynamic behavior of reversible oxygen migration in irradiated-annealed high temperature superconducting wires
Authors: Zhang Yi , Rupich M. W. , Solovyov Vyacheslav , Li Qiang , Goyal Amit
Published: September 2020

We use atomically resolved scanning transmission electron microscopy and electron energy loss spectroscopy to determine the atomic-scale structural, chemical and electronic properties of artificial engineered defects in irradiated-annealed high temperature superconducting wires based on epitaxial Y(Dy)BCO film. We directly probe the oxygen vacancy defects in both plane and chain sites after irradiation with 18-meV Au ions. The plane site vacancies are reoccupied during post-annealing treatment. Our results demonstrate the dynamic reversible behavior of oxygen point defects, which explains the depression and recovery of self-field critical current and critical temperature in irradiation-annealing process. These findings reveal the strong effect of oxygen vacancies in different sites on the superconductivity properties of irradiated Y(Dy)BCO film, and provide important insights into defects engineering of 2G HTS coil wires.
Author Correction: Synthetic antigen-binding fragments (Fabs) against S. mutans and S. sobrinus inhibit caries formation
Authors: Alam Md. Kausar , Zheng Li , Liu Ruirui , Papagerakis Silvana , Papagerakis Petros , Geyer C. Ronald
Published: September 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Discovery of a selective, state-independent inhibitor of NaV1.7 by modification of guanidinium toxins
Authors: Pajouhesh H. , Beckley J. T. , Delwig A. , Hajare H. S. , Luu G. , Monteleone D. , Zhou X. , Ligutti J. , Amagasu S. , Moyer B. D. , Yeomans D. C. , Du Bois J. , Mulcahy J. V.
Published: September 2020

The voltage-gated sodium channel isoform NaV1.7 is highly expressed in dorsal root ganglion neurons and is obligatory for nociceptive signal transmission. Genetic gain-of-function and loss-of-function NaV1.7 mutations have been identified in select individuals, and are associated with episodic extreme pain disorders and insensitivity to pain, respectively. These findings implicate NaV1.7 as a key pharmacotherapeutic target for the treatment of pain. While several small molecules targeting NaV1.7 have been advanced to clinical development, no NaV1.7-selective compound has shown convincing efficacy in clinical pain applications. Here we describe the discovery and characterization of ST-2262, a NaV1.7 inhibitor that blocks the extracellular vestibule of the channel with an IC50 of 72 nM and greater than 200-fold selectivity over off-target sodium channel isoforms, NaV1.1–1.6 and NaV1.8. In contrast to other NaV1.7 inhibitors that preferentially inhibit the inactivated state of the channel, ST-2262 is equipotent in a protocol that favors the resting state of the channel, a protocol that favors the inactivated state, and a high frequency protocol. In a non-human primate study, animals treated with ST-2262 exhibited reduced sensitivity to noxious heat. These findings establish the extracellular vestibule of the sodium channel as a viable receptor site for the design of selective ligands targeting NaV1.7.
Novel role of lncRNA CHRF in cisplatin resistance of ovarian cancer is mediated by miR-10b induced EMT and STAT3 signaling
Authors: Tan Wen-Xi , Sun Ge , Shangguan Meng-Yuan , Gui Zhi , Bao Yang , Li Yu-Feng , Jia Zan-Hui
Published: September 2020

Ovarian Cancer (OC) is a highly lethal gynecological cancer which often progresses through acquired resistance against the administered therapy. Cisplatin is a common therapeutic for the treatment of OC patients and therefore it is critical to understand the mechanisms of resistance against this drug. We studied a paired cell line consisting of parental and cisplatin resistant (CR) derivative ES2 OC cells, and found a number of dysregulated lncRNAs, with CHRF being the most significantly upregulated lncRNA in CR ES2 cells. The findings corroborated in human patient samples and CHRF was significantly elevated in OC patients with resistant disease. CHRF was also found to be elevated in patients with liver metastasis. miR-10b was found to be mechanistically involved in CHRF mediated cisplatin resistance. It induced resistance in not only ES2 but also OVCAR and SKOV3 OC cells. Induction of epithelial-to-mesenchymal-transition (EMT) and activation of STAT3 signaling were determined to be the mechanisms underlying the CHRF-miR-10b axis-mediated cisplatin resistance. Down-regulation of CHRF reversed EMT, STAT3 activation and the resulting cisplatin resistance, which could be attenuated by miR-10b. The results were also validated in an in vivo cisplatin resistance model wherein CR cells were associated with increased tumor burden, CHRF downregulation associated with decreased tumor burden and miR-10b again attenuated the CHRF downregulation effects. Our results support a novel role of lncRNA CHRF in cisplatin resistance of OC and establish CHRF-miR-10b signaling as a putative therapeutic target for sensitizing resistant OC cells.
Effectiveness and moderators of individual cognitive behavioral therapy versus treatment as usual in clinically depressed adolescents: a randomized controlled trial
Authors: Stikkelbroek Yvonne , Vink Gerko , Nauta Maaike H. , Bottelier Marco A. , Vet Leonieke J. J. , Lont Cathelijne M. , van Baar Anneloes L. , Bodden Denise H. M.
Published: September 2020

We examined if manualized cognitive behavioral therapy (CBT) was more effective than Treatment As Usual (TAU) for clinically depressed adolescents within routine care. This multisite Randomized controlled trail included 88 clinically depressed adolescents (aged 12–21 years) randomly assigned to CBT or TAU. Multiple assessments (pre-, post treatment and six-month follow-up) were done using semi-structured interviews, questionnaires and ratings and multiple informants. The primary outcome was depressive or dysthymic disorder based on the KSADS. Completers, CBT (n = 19) and TAU (n = 26), showed a significant reduction of affective diagnoses at post treatment (76% versus 76%) and after six months (90% versus 79%). Intention-to-treat analyses on depressive symptoms showed that 41.6% within CBT and 31.8% within the TAU condition was below clinical cut-off at post treatment and after six-months, respectively 61.4% and 47.7%. No significant differences in self-reported depressive symptoms between CBT and TAU were found. No prediction or moderation effects were found for age, gender, child/parent educational level, suicidal criteria, comorbidity, and severity of depression. We conclude that CBT did not outperform TAU in clinical practice in the Netherlands. Both treatments were found to be suitable to treat clinically referred depressed adolescents. CBT needs further improvement to decrease symptom levels below the clinical cut-off at post treatment.
Representation of edges, head direction, and swimming kinematics in the brain of freely-navigating fish
Authors: Vinepinsky Ehud , Cohen Lear , Perchik Shay , Ben-Shahar Ohad , Donchin Opher , Segev Ronen
Published: September 2020

Like most animals, the survival of fish depends on navigation in space. This capacity has been documented in behavioral studies that have revealed navigation strategies. However, little is known about how freely swimming fish represent space and locomotion in the brain to enable successful navigation. Using a wireless neural recording system, we measured the activity of single neurons in the goldfish lateral pallium, a brain region known to be involved in spatial memory and navigation, while the fish swam freely in a two-dimensional water tank. We found that cells in the lateral pallium of the goldfish encode the edges of the environment, the fish head direction, the fish swimming speed, and the fish swimming velocity-vector. This study sheds light on how information related to navigation is represented in the brain of fish and addresses the fundamental question of the neural basis of navigation in this group of vertebrates.
A laser emitting contact lens for eye tracking
Authors: Khaldi A. , Daniel E. , Massin L. , Kärnfelt C. , Ferranti F. , Lahuec C. , Seguin F. , Nourrit V. , de Bougrenet de la Tocnaye J.-L.
Published: September 2020

In this paper, we present the first realisation and experimentation of a new eye tracking system using an infrared (iR) laser pointer embedded into a wireless smart contact lens. We denote this contact lens prototype as the cyclops lens, in reference to the famous hero of the X-Men comics. The full eye tracker device combines the smart contact lens and its eyewear, which provides a primary source of energy and the beam detection system. We detail the assembling and encapsulation process of the main functionalities into the contact lens and present how a gaze tracking system is achieved, compared to existing conventional eye-tracking ones. Finally, we discuss future technical improvements.
The olivocochlear reflex strength in awake chinchillas is relevant for behavioural performance during visual selective attention with auditory distractors
Authors: Bowen Macarena , Terreros Gonzalo , Moreno-Gómez Felipe N. , Ipinza Macarena , Vicencio Sergio , Robles Luis , Delano Paul H.
Published: September 2020

The auditory efferent system comprises descending projections from the cerebral cortex to subcortical nuclei, reaching the cochlear receptor through olivocochlear fibres. One of the functions attributed to this corticofugal system is to suppress irrelevant sounds during selective attention to visual stimuli. Medial olivocochlear neurons can also be activated by sounds through a brainstem reflex circuit. Whether the individual variability of this reflex is related to the cognitive capacity to suppress auditory stimuli is still controversial. Here we propose that the individual strength per animal of the olivocochlear reflex is correlated with the ability to suppress auditory distractors during visual attention in awake chinchillas. The olivocochlear reflex was elicited with a contralateral broad-band noise at ~ 60 dB and ipsilateral distortion product otoacoustic emissions were obtained at different frequencies (1–8 kHz). Fourteen chinchillas were evaluated in a behavioural protocol of visual attention with broad-band noise and chinchilla vocalizations as auditory distractors. Results show that the behavioural performance was affected by both distractors and that the magnitudes of the olivocochlear reflex evaluated at multiple frequencies were relevant for behavioural performance during visual discrimination with auditory distractors. These results stress the ecological relevance of the olivocochlear system for suppressing natural distractors.
Membrane disruption, but not metabolic rewiring, is the key mechanism of anticancer-action of FASN-inhibitors: a multi-omics analysis in ovarian cancer
Authors: Grunt Thomas W. , Slany Astrid , Semkova Mariya , Colomer Ramón , López-Rodríguez María Luz , Wuczkowski Michael , Wagner Renate , Gerner Christopher , Stübiger Gerald
Published: September 2020

Fatty-acid(FA)-synthase(FASN) is a druggable lipogenic oncoprotein whose blockade causes metabolic disruption. Whether drug-induced metabolic perturbation is essential for anticancer drug-action, or is just a secondary—maybe even a defence response—is still unclear. To address this, SKOV3 and OVCAR3 ovarian cancer(OC) cell lines with clear cell and serous histology, two main OC subtypes, were exposed to FASN-inhibitor G28UCM. Growth-inhibition was compared with treatment-induced cell-metabolomes, lipidomes, proteomes and kinomes. SKOV3 and OVCAR3 were equally sensitive to low-dose G28UCM, but SKOV3 was more resistant than OVCAR3 to higher concentrations. Metabolite levels generally decreased upon treatment, but individual acylcarnitines, glycerophospholipids, sphingolipids, amino-acids, biogenic amines, and monosaccharides reacted differently. Drug-induced effects on central-carbon-metabolism and oxidative-phosphorylation (OXPHOS) were essentially different in the two cell lines, since drug-naïve SKOV3 are known to prefer glycolysis, while OVCAR3 favour OXPHOS. Moreover, drug-dependent increase of desaturases and polyunsaturated-fatty-acids (PUFAs) were more pronounced in SKOV3 and appear to correlate with G28UCM-tolerance. In contrast, expression and phosphorylation of proteins that control apoptosis, FA synthesis and membrane-related processes (beta-oxidation, membrane-maintenance, transport, translation, signalling and stress-response) were concordantly affected. Overall, membrane-disruption and second-messenger-silencing were crucial for anticancer drug-action, while metabolic-rewiring was only secondary and may support high-dose-FASN-inhibitor-tolerance. These findings may guide future anti-metabolic cancer intervention.