bluuebunny/crossref_metadata_2025 huggingface dataset:
Eddy Compensation Dampens Southern Ocean Sea Surface Temperature Response to Westerly Wind Trends
Authors: Doddridge Edward W. , Marshall John , Song Hajoon , Campin Jean‐Michel , Kelley Maxwell , Nazarenko Larissa
Published: April 2019

Anthropogenic influences have led to a strengthening and poleward shift of westerly winds over the Southern Ocean, especially during austral summer. We use observations, an idealized eddy‐resolving ocean sea ice channel model, and a global coupled model to explore the Southern Ocean response to a step change in westerly winds. Previous work hypothesized a two time scale response for sea surface temperature. Initially, Ekman transport cools the surface before sustained upwelling causes warming on decadal time scales. The fast response is robust across our models and the observations: We find Ekman‐driven cooling in the mixed layer, mixing‐driven warming below the mixed layer, and a small upwelling‐driven warming at the temperature inversion. The long‐term response is inaccessible from observations. Neither of our models shows a persistent upwelling anomaly, or long‐term, upwelling‐driven subsurface warming. Mesoscale eddies act to oppose the anomalous wind‐driven upwelling, through a process known as eddy compensation, thereby preventing long‐term warming.
“CandidatusMacondimonas diazotrophica”, a novel gammaproteobacterial genus dominating crude-oil-contaminated coastal sediments
Authors: Karthikeyan Smruthi , Rodriguez-R Luis M , Heritier-Robbins Patrick , Kim Minjae , Overholt Will A , Gaby John C , Hatt Janet K , Spain Jim C , Rosselló-Móra Ramon , Huettel Markus , Kostka Joel E , Konstantinidis Konstantinos T
Published: April 2019

Modeling crude-oil biodegradation in sediments remains a challenge due in part to the lack of appropriate model organisms. Here we report the metagenome-guided isolation of a novel organism that represents a phylogenetically narrow (>97% 16S rRNA gene identity) group of previously uncharacterized, crude-oil degraders. Analysis of available sequence data showed that these organisms are highly abundant in oiled sediments of coastal marine ecosystems across the world, often comprising ~30% of the total community, and virtually absent in pristine sediments or seawater. The isolate genome encodes functional nitrogen fixation and hydrocarbon degradation genes together with putative genes for biosurfactant production that apparently facilitate growth in the typically nitrogen-limited, oiled environment. Comparisons to available genomes revealed that this isolate represents a novel genus within the Gammaproteobacteria, for which we propose the provisional name “Candidatus Macondimonas diazotrophica” gen. nov., sp. nov. “Ca. M. diazotrophica” appears to play a key ecological role in the response to oil spills around the globe and could be a promising model organism for studying ecophysiological responses to oil spills.
Rare earth element alcohol dehydrogenases widely occur among globally distributed, numerically abundant and environmentally important microbes
Authors: Huang Jing , Yu Zheng , Groom Joseph , Cheng Jan-Fang , Tarver Angela , Yoshikuni Yasuo , Chistoserdova Ludmila
Published: April 2019

Lanthanides (Ln3+), known as rare earth elements, have recently emerged as enzyme cofactors, contrary to prior assumption of their biological inertia. Several bacterial alcohol dehydrogenases have been characterized so far that depend on Ln3+ for activity and expression, belonging to the methanol dehydrogenase clade XoxF and the ethanol dehydrogenase clade ExaF/PedH. Here we compile an inventory of genes potentially encoding Ln3+-dependent enzymes, closely related to the previously characterized XoxF and ExaF/PedH enzymes. We demonstrate their wide distribution among some of the most numerically abundant and environmentally important taxa, such as the phylogenetically disparate rhizobial species and metabolically versatile bacteria inhabiting world’s oceans, suggesting that reliance on Ln3+-mediated biochemistry is much more widespread in the microbial world than previously assumed. Through protein expression and analysis, we here more than double the extant collection of the biochemically characterized Ln3+-dependent enzymes, demonstrating a range of catalytic properties and substrate and cofactor specificities. Many of these enzymes reveal propensity for oxidation of methanol. This observation, in combination with genome-based reconstruction of methylotrophy pathways for select species suggests a much wider occurrence of this metabolic capability among bacterial species, and thus further suggests the importance of methylated compounds as parts of the global carbon cycling.
Electronic transport in planar atomic-scale structures measured by two-probe scanning tunneling spectroscopy
Authors: Kolmer Marek , Brandimarte Pedro , Lis Jakub , Zuzak Rafal , Godlewski Szymon , Kawai Hiroyo , Garcia-Lekue Aran , Lorente Nicolas , Frederiksen Thomas , Joachim Christian , Sanchez-Portal Daniel , Szymonski Marek
Published: April 2019

Miniaturization of electronic circuits into the single-atom level requires novel approaches to characterize transport properties. Due to its unrivaled precision, scanning probe microscopy is regarded as the method of choice for local characterization of atoms and single molecules supported on surfaces. Here we investigate electronic transport along the anisotropic germanium (001) surface with the use of two-probe scanning tunneling spectroscopy and first-principles transport calculations. We introduce a method for the determination of the transconductance in our two-probe experimental setup and demonstrate how it captures energy-resolved information about electronic transport through the unoccupied surface states. The sequential opening of two transport channels within the quasi-one-dimensional Ge dimer rows in the surface gives rise to two distinct resonances in the transconductance spectroscopic signal, consistent with phase-coherence lengths of up to 50 nm and anisotropic electron propagation. Our work paves the way for the electronic transport characterization of quantum circuits engineered on surfaces.
The parasitic worm product ES-62 normalises the gut microbiota bone marrow axis in inflammatory arthritis
Authors: Doonan James , Tarafdar Anuradha , Pineda Miguel A. , Lumb Felicity E. , Crowe Jenny , Khan Aneesah M. , Hoskisson Paul A. , Harnett Margaret M. , Harnett William
Published: April 2019

The human immune system has evolved in the context of our colonisation by bacteria, viruses, fungi and parasitic helminths. Reflecting this, the rapid eradication of pathogens appears to have resulted in reduced microbiome diversity and generation of chronically activated immune systems, presaging the recent rise of allergic, autoimmune and metabolic disorders. Certainly, gastrointestinal helminths can protect against gut and lung mucosa inflammatory conditions by modulating the microbiome and suppressing the chronic inflammation associated with dysbiosis. Here, we employ ES-62, an immunomodulator secreted by tissue-dwellingAcanthocheilonema viteaeto show that helminth-modulation of the gut microbiome does not require live infection with gastrointestinal-based worms nor is protection restricted to mucosal diseases. Specifically, subcutaneous administration of this defined immunomodulator affords protection against joint disease in collagen-induced arthritis, a mouse model of rheumatoid arthritis, which is associated with normalisation of gut microbiota and prevention of loss of intestinal barrier integrity.
Adjustment for index event bias in genome-wide association studies of subsequent events
Authors: Dudbridge Frank , Allen Richard J. , Sheehan Nuala A. , Schmidt A. Floriaan , Lee James C. , Jenkins R. Gisli , Wain Louise V. , Hingorani Aroon D. , Patel Riyaz S.
Published: April 2019

Following numerous genome-wide association studies of disease susceptibility, there is increasing interest in genetic associations with prognosis, survival or other subsequent events. Such associations are vulnerable to index event bias, by which selection of subjects according to disease status creates biased associations if common causes of incidence and prognosis are not accounted for. We propose an adjustment for index event bias using the residuals from the regression of genetic effects on prognosis on genetic effects on incidence. Our approach eliminates this bias when direct genetic effects on incidence and prognosis are independent, and otherwise reduces bias in realistic situations. In a study of idiopathic pulmonary fibrosis, we reverse a paradoxical association of the strong susceptibility gene MUC5B with increased survival, suggesting instead a significant association with decreased survival. In re-analysis of a study of Crohn’s disease prognosis, four regions remain associated at genome-wide significance but with increased standard errors.
FoxK1 and FoxK2 in insulin regulation of cellular and mitochondrial metabolism
Authors: Sakaguchi Masaji , Cai Weikang , Wang Chih-Hao , Cederquist Carly T. , Damasio Marcos , Homan Erica P. , Batista Thiago , Ramirez Alfred K. , Gupta Manoj K. , Steger Martin , Wewer Albrechtsen Nicolai J. , Singh Shailendra Kumar , Araki Eiichi , Mann Matthias , Enerbäck Sven , Kahn C. Ronald
Published: April 2019

A major target of insulin signaling is the FoxO family of Forkhead transcription factors, which translocate from the nucleus to the cytoplasm following insulin-stimulated phosphorylation. Here we show that the Forkhead transcription factors FoxK1 and FoxK2 are also downstream targets of insulin action, but that following insulin stimulation, they translocate from the cytoplasm to nucleus, reciprocal to the translocation of FoxO1. FoxK1/FoxK2 translocation to the nucleus is dependent on the Akt-mTOR pathway, while its localization to the cytoplasm in the basal state is dependent on GSK3. Knockdown of FoxK1 and FoxK2 in liver cells results in upregulation of genes related to apoptosis and down-regulation of genes involved in cell cycle and lipid metabolism. This is associated with decreased cell proliferation and altered mitochondrial fatty acid metabolism. Thus, FoxK1/K2 are reciprocally regulated to FoxO1 following insulin stimulation and play a critical role in the control of apoptosis, metabolism and mitochondrial function.
Unifying scrambling, thermalization and entanglement through measurement of fidelity out-of-time-order correlators in the Dicke model
Authors: Lewis-Swan R. J. , Safavi-Naini A. , Bollinger J. J. , Rey A. M.
Published: April 2019

Scrambling is the process by which information stored in local degrees of freedom spreads over the many-body degrees of freedom of a quantum system, becoming inaccessible to local probes and apparently lost. Scrambling and entanglement can reconcile seemingly unrelated behaviors including thermalization of isolated quantum systems and information loss in black holes. Here, we demonstrate that fidelity out-of-time-order correlators (FOTOCs) can elucidate connections between scrambling, entanglement, ergodicity and quantum chaos (butterfly effect). We compute FOTOCs for the paradigmatic Dicke model, and show they can measure subsystem Rényi entropies and inform about quantum thermalization. Moreover, we illustrate why FOTOCs give access to a simple relation between quantum and classical Lyapunov exponents in a chaotic system without finite-size effects. Our results open a path to experimental use FOTOCs to explore scrambling, bounds on quantum information processing and investigation of black hole analogs in controllable quantum systems.
The class 3 PI3K coordinates autophagy and mitochondrial lipid catabolism by controlling nuclear receptor PPARα
Authors: Iershov Anton , Nemazanyy Ivan , Alkhoury Chantal , Girard Muriel , Barth Esther , Cagnard Nicolas , Montagner Alexandra , Chretien Dominique , Rugarli Elena I. , Guillou Herve , Pende Mario , Panasyuk Ganna
Published: April 2019

The class 3 phosphoinositide 3-kinase (PI3K) is required for lysosomal degradation by autophagy and vesicular trafficking, assuring nutrient availability. Mitochondrial lipid catabolism is another energy source. Autophagy and mitochondrial metabolism are transcriptionally controlled by nutrient sensing nuclear receptors. However, the class 3 PI3K contribution to this regulation is unknown. We show that liver-specific inactivation of Vps15, the essential regulatory subunit of the class 3 PI3K, elicits mitochondrial depletion and failure to oxidize fatty acids. Mechanistically, transcriptional activity of Peroxisome Proliferator Activated Receptor alpha (PPARα), a nuclear receptor orchestrating lipid catabolism, is blunted in Vps15-deficient livers. We find PPARα repressors Histone Deacetylase 3 (Hdac3) and Nuclear receptor co-repressor 1 (NCoR1) accumulated in Vps15-deficient livers due to defective autophagy. Activation of PPARα or inhibition of Hdac3 restored mitochondrial biogenesis and lipid oxidation in Vps15-deficient hepatocytes. These findings reveal roles for the class 3 PI3K and autophagy in transcriptional coordination of mitochondrial metabolism.
Bidirectional contraction of a type six secretion system
Authors: Szwedziak Piotr , Pilhofer Martin
Published: April 2019

Contractile injection systems (CISs) mediate cell-cell interactions by a phage tail-like apparatus. Their conserved mechanism relies on the anchoring of the proximal end of a sheath-tube module to a membrane, followed by contraction of the sheath towards the attachment site and ejection of the inner tube. Here we reveal a major variation of the CIS mechanism in the type six secretion system (T6SS) of enteroaggregative Escherichia coli (EAEC). We show that both ends of the sheath-tube module are attached to opposite sides of the cell, enabling the structure to contract in two opposite directions. The protein TssA1 mediates the interaction of the distal end with the cell envelope, the termination of tail elongation, and non-canonical contraction towards the distal end. We provide a framework for the molecular processes at the T6SS distal end. Further research will address whether bidirectional contraction allows for bidirectional effector secretion. The unrecognized concept of non-canonical contractions could be relevant to biofilms of the human intestine.
Evidence for a prolonged Permian–Triassic extinction interval from global marine mercury records
Authors: Shen Jun , Chen Jiubin , Algeo Thomas J. , Yuan Shengliu , Feng Qinglai , Yu Jianxin , Zhou Lian , O’Connell Brennan , Planavsky Noah J.
Published: April 2019

The latest Permian mass extinction, the most devastating biocrisis of the Phanerozoic, has been widely attributed to eruptions of the Siberian Traps Large Igneous Province, although evidence of a direct link has been scant to date. Here, we measure mercury (Hg), assumed to reflect shifts in volcanic activity, across the Permian-Triassic boundary in ten marine sections across the Northern Hemisphere. Hg concentration peaks close to the Permian-Triassic boundary suggest coupling of biotic extinction and increased volcanic activity. Additionally, Hg isotopic data for a subset of these sections provide evidence for largely atmospheric rather than terrestrial Hg sources, further linking Hg enrichment to increased volcanic activity. Hg peaks in shallow-water sections were nearly synchronous with the end-Permian extinction horizon, while those in deep-water sections occurred tens of thousands of years before the main extinction, possibly supporting a globally diachronous biotic turnover and protracted mass extinction event.
New frontiers for the materials genome initiative
Authors: de Pablo Juan J. , Jackson Nicholas E. , Webb Michael A. , Chen Long-Qing , Moore Joel E. , Morgan Dane , Jacobs Ryan , Pollock Tresa , Schlom Darrell G. , Toberer Eric S. , Analytis James , Dabo Ismaila , DeLongchamp Dean M. , Fiete Gregory A. , Grason Gregory M. , Hautier Geoffroy , Mo Yifei , Rajan Krishna , Reed Evan J. , Rodriguez Efrain , Stevanovic Vladan , Suntivich Jin , Thornton Katsuyo , Zhao Ji-Cheng
Published: April 2019

The Materials Genome Initiative (MGI) advanced a new paradigm for materials discovery and design, namely that the pace of new materials deployment could be accelerated through complementary efforts in theory, computation, and experiment. Along with numerous successes, new challenges are inviting researchers to refocus the efforts and approaches that were originally inspired by the MGI. In May 2017, the National Science Foundation sponsored the workshop “Advancing and Accelerating Materials Innovation Through the Synergistic Interaction among Computation, Experiment, and Theory: Opening New Frontiers” to review accomplishments that emerged from investments in science and infrastructure under the MGI, identify scientific opportunities in this new environment, examine how to effectively utilize new materials innovation infrastructure, and discuss challenges in achieving accelerated materials research through the seamless integration of experiment, computation, and theory. This article summarizes key findings from the workshop and provides perspectives that aim to guide the direction of future materials research and its translation into societal impacts.
Multi-year whole-blood transcriptome data for the study of onset and progression of Parkinson’s Disease
Authors: Valentine Matthew N. Z. , Hashimoto Kosuke , Fukuhara Takeshi , Saiki Shinji , Ishikawa Kei-ichi , Hattori Nobutaka , Carninci Piero
Published: April 2019

Parkinson’s disease (PD) is an age-related, chronic and progressive neurodegenerative disorder characterized by a loss of multifocal neurons, resulting in both non-motor and motor symptoms. While several genetic and environmental contributory risk factors have been identified, more exact methods for diagnosing and assessing prognosis of PD have yet to be established. Here we describe the generation and validation of a dataset comprising whole-blood transcriptomes originally intended for use in detection of blood biomarkers and transcriptomic network changes indicative of PD. Whole-blood samples extracted from both early-stage PD patients and healthy controls were sequenced using no-amplification non-tagging cap analysis of gene expression (nAnT-iCAGE) to analyse differences in global RNA expression patterns across the conditions. Subsequent sampling of a subset of PD patients one-year later provides the opportunity to study changes in transcriptomes arising due to disease progression.
Multi-channel EEG recordings during a sustained-attention driving task
Authors: Cao Zehong , Chuang Chun-Hsiang , King Jung-Kai , Lin Chin-Teng
Published: April 2019

We describe driver behaviour and brain dynamics acquired from a 90-minute sustained-attention task in an immersive driving simulator. The data included 62 sessions of 32-channel electroencephalography (EEG) data for 27 subjects driving on a four-lane highway who were instructed to keep the car cruising in the centre of the lane. Lane-departure events were randomly induced to cause the car to drift from the original cruising lane towards the left or right lane. A complete trial included events with deviation onset, response onset, and response offset. The next trial, in which the subject was instructed to drive back to the original cruising lane, began 5–10 seconds after finishing the previous trial. We believe that this dataset will lead to the development of novel neural processing methodology that can be used to index brain cortical dynamics and detect driving fatigue and drowsiness. This publicly available dataset will be beneficial to the neuroscience and brain-computer interface communities.
Dry season habitat use of fishes in an Australian tropical river
Authors: Keller K. , Allsop Q. , Brim Box J. , Buckle D. , Crook D. A. , Douglas M. M. , Jackson S. , Kennard M. J. , Luiz O. J. , Pusey B. J. , Townsend S. A. , King A. J.
Published: April 2019

The modification of river flow regimes poses a significant threat to the world’s freshwater ecosystems. Northern Australia’s freshwater resources, particularly dry season river flows, are being increasingly modified to support human development, potentially threatening aquatic ecosystems and biodiversity, including fish. More information is urgently needed on the ecology of fishes in this region, including their habitat requirements, to support water policy and management to ensure future sustainable development. This study used electrofishing and habitat survey methods to quantify the dry season habitat use of 20 common freshwater fish taxa in the Daly River in Australia’s wet-dry tropics. Of twenty measured habitat variables, water depth and velocity were the two most important factors discriminating fish habitat use for the majority of taxa. Four distinct fish habitat guilds were identified, largely classified according to depth, velocity and structural complexity. Ontogenetic shifts in habitat use were also observed in three species. This study highlights the need to maintain dry season river flows that support a diversity of riverine mesohabitats for freshwater fishes. In particular, shallow fast-flowing areas provided critical nursery and refuge habitats for some species, but are vulnerable to water level reductions due to water extraction. By highlighting the importance of a diversity of habitats for fishes, this study assists water managers in future decision making on the ecological risks of water extractions from tropical rivers, and especially the need to maintain dry season low flows to protect the habitats of native fish.
Point-dipole approximation for small systems of strongly coupled radiating nanorods
Authors: Watson Derek W. , Jenkins Stewart D. , Fedotov Vassili A. , Ruostekoski Janne
Published: April 2019

Systems of closely-spaced resonators can be strongly coupled by interactions mediated by scattered electromagnetic fields. In large systems the resulting response has been shown to be more sensitive to these collective interactions than to the detailed structure of individual resonators. Attempts to describe such systems have resulted in point-dipole approximations to resonators that are computationally efficient for large resonator ensembles. Here we provide a detailed study for the validity of point dipole approximations in small systems of strongly coupled plasmonic nanorods, including the cases of both super-radiant and subradiant excitations, where the characteristics of the excitation depends on the spatial separation between the nanorods. We show that over an appreciable range of rod lengths centered on 210 nm, when the relative separation kl in terms of the resonance wave number of light k satisfies $$kl\gtrsim \pi /2$$
k
l
≳
π
/
2
, the point electric dipole model becomes accurate. However, when the resonators are closer, the finite-size and geometry of the resonators modifies the excitation modes, in particular the cooperative mode line shifts of the point dipole approximation begin to rapidly diverge at small separations. We also construct simplified effective models by describing a pair of nanorods as a single effective metamolecule.
Deletion of biosynthetic genes, specific SNP patterns and differences in transcript accumulation cause variation in hydroxynitrile glucoside content in barley cultivars
Authors: Ehlert Marcus , Jagd Lea Møller , Braumann Ilka , Dockter Christoph , Crocoll Christoph , Motawia Mohammed Saddik , Møller Birger Lindberg , Lyngkjær Michael Foged
Published: April 2019

Barley (Hordeum vulgare L.) produces five leucine-derived hydroxynitrile glucosides, potentially involved in alleviating pathogen and environmental stresses. These compounds include the cyanogenic glucoside epiheterodendrin. The biosynthetic genes are clustered. Total hydroxynitrile glucoside contents were previously shown to vary from zero to more than 10,000 nmoles g−1 in different barley lines. To elucidate the cause of this variation, the biosynthetic genes from the high-level producer cv. Mentor, the medium-level producer cv. Pallas, and the zero-level producer cv. Emir were investigated. In cv. Emir, a major deletion in the genome spanning most of the hydroxynitrile glucoside biosynthetic gene cluster was identified and explains the complete absence of hydroxynitrile glucosides in this cultivar. The transcript levels of the biosynthetic genes were significantly higher in the high-level producer cv. Mentor compared to the medium-level producer cv. Pallas, indicating transcriptional regulation as a contributor to the variation in hydroxynitrile glucoside levels. A correlation between distinct single nucleotide polymorphism (SNP) patterns in the biosynthetic gene cluster and the hydroxynitrile glucoside levels in 227 barley lines was identified. It is remarkable that in spite of the demonstrated presence of a multitude of SNPs and differences in transcript levels, the ratio between the five hydroxynitrile glucosides is maintained across all the analysed barley lines. This implies the involvement of a stably assembled multienzyme complex.
Viscoelastic biomarker for differentiation of benign and malignant breast lesion in ultra- low frequency range
Authors: Nabavizadeh Alireza , Bayat Mahdi , Kumar Viksit , Gregory Adriana , Webb Jeremy , Alizad Azra , Fatemi Mostafa
Published: April 2019

Benign and malignant tumors differ in the viscoelastic properties of their cellular microenvironments and in their spatiotemporal response to very low frequency stimuli. These differences can introduce a unique viscoelastic biomarker in differentiation of benign and malignant tumors. This biomarker may reduce the number of unnecessary biopsies in breast patients. Although different methods have been developed so far for this purpose, none of them have focused on in vivo and in situ assessment of local viscoelastic properties in the ultra-low (sub-Hertz) frequency range. Here we introduce a new, noninvasive model-free method called Loss Angle Mapping (LAM). We assessed the performance results on 156 breast patients. The method was further improved by detection of out-of-plane motion using motion compensation cross correlation method (MCCC). 45 patients met this MCCC criterion and were considered for data analysis. Among this population, we found 77.8% sensitivity and 96.3% specificity (p < 0.0001) in discriminating between benign and malignant tumors using logistic regression method regarding the pre known information about the BIRADS number and size. The accuracy and area under the ROC curve, AUC, was 88.9% and 0.94, respectively. This method opens new avenues to investigate the mechanobiology behavior of different tissues in a frequency range that has not yet been explored in any in vivo patient studies.
Metabolic resistance of the D-peptide RD2 developed for direct elimination of amyloid-β oligomers
Authors: Elfgen Anne , Hupert Michelle , Bochinsky Kevin , Tusche Markus , González de San Román Martin Estibaliz , Gering Ian , Sacchi Silvia , Pollegioni Loredano , Huesgen Pitter F. , Hartmann Rudolf , Santiago-Schübel Beatrix , Kutzsche Janine , Willbold Dieter
Published: April 2019

Alzheimer’s disease (AD) is a neurodegenerative disorder leading to dementia. Aggregation of the amyloid-β peptide (Aβ) plays an important role in the disease, with Aβ oligomers representing the most toxic species. Previously, we have developed the Aβ oligomer eliminating therapeutic compound RD2 consisting solely of D-enantiomeric amino acid residues. RD2 has been described to have an oral bioavailability of more than 75% and to improve cognition in transgenic Alzheimer’s disease mouse models after oral administration. In the present study, we further examined the stability of RD2 in simulated gastrointestinal fluids, blood plasma and liver microsomes. In addition, we have examined whether RD2 is a substrate for the human D-amino acid oxidase (hDAAO). Furthermore, metabolite profiles of RD2 incubated in human, rodent and non-rodent liver microsomes were compared across species to search for human-specific metabolites that might possibly constitute a threat when applying the compound in humans. RD2 was remarkably resistant against metabolization in all investigated media and not converted by hDAAO. Moreover, RD2 did not influence the activity of any of the tested enzymes. In conclusion, the high stability and the absence of relevant human-specific metabolites support RD2 to be safe for oral administration in humans.
Clustering of integrin β cytoplasmic domains triggers nascent adhesion formation and reveals a protozoan origin of the integrin-talin interaction
Authors: Baade Timo , Paone Christoph , Baldrich Adrian , Hauck Christof R.
Published: April 2019

Integrins and integrin-dependent cell-matrix adhesions are essential for a number of physiological processes. Integrin function is tightly regulated via binding of cytoplasmic proteins to integrin intracellular domains. Yet, the complexity of cell-matrix adhesions in mammals, with more than 150 core adhesome proteins, complicates the analysis of integrin-associated protein complexes. Interestingly, the evolutionary origin of integrins dates back before the transition from unicellular life to complex multicellular animals. Though unicellular relatives of metazoa have a less complex adhesome, nothing is known about the initial steps of integrin activation and adhesion complex assembly in protozoa. Therefore, we developed a minimal, microscope-based system using chimeric integrins to investigate receptor-proximal events during focal adhesion assembly. Clustering of the human integrin β1 tail led to recruitment of talin, kindlin, and paxillin and mutation of the known talin binding site abolished recruitment of this protein. Proteins indirectly linked to integrins, such as vinculin, migfilin, p130CAS, or zyxin were not enriched around the integrin β1 tail. With the exception of integrin β4 and integrin β8, the cytoplasmic domains of all human integrin β subunits supported talin binding. Likewise, the cytoplasmic domains of integrin β subunits expressed by the protozoan Capsaspora owczarzaki readily recruited talin and this interaction was based on an evolutionary conserved NPXY/F amino acid motif. The results we present here validate the use of our novel microscopic assay to uncover details of integrin-based protein-protein interactions in a cellular context and suggest that talin binding to integrin β cytoplasmic tails is an ancient feature of integrin regulation.
High-Throughput, Time-Resolved Mechanical Phenotyping of Prostate Cancer Cells
Authors: Belotti Yuri , Tolomeo Serenella , Conneely Michael J. , Huang Tianjun , McKenna Stephen J. , Nabi Ghulam , McGloin David
Published: April 2019

Worldwide, prostate cancer sits only behind lung cancer as the most commonly diagnosed form of the disease in men. Even the best diagnostic standards lack precision, presenting issues with false positives and unneeded surgical intervention for patients. This lack of clear cut early diagnostic tools is a significant problem. We present a microfluidic platform, the Time-Resolved Hydrodynamic Stretcher (TR-HS), which allows the investigation of the dynamic mechanical response of thousands of cells per second to a non-destructive stress. The TR-HS integrates high-speed imaging and computer vision to automatically detect and track single cells suspended in a fluid and enables cell classification based on their mechanical properties. We demonstrate the discrimination of healthy and cancerous prostate cell lines based on the whole-cell, time-resolved mechanical response to a hydrodynamic load. Additionally, we implement a finite element method (FEM) model to characterise the forces responsible for the cell deformation in our device. Finally, we report the classification of the two different cell groups based on their time-resolved roundness using a decision tree classifier. This approach introduces a modality for high-throughput assessments of cellular suspensions and may represent a viable application for the development of innovative diagnostic devices.
Crystalline orientation control of the platelet Nd2Fe14B phase to produce magnetic anisotropy via electromagnetic vibration processing
Authors: Li Mingjun , Tamura Takuya
Published: April 2019

Controlled crystalline orientation of the discontinuous phase in a composite enables the production of improved anisotropic properties, e.g., well-aligned Nd2Fe14B platelets by hot pressing and then soaking in a low-melting Nd-Cu eutectic melt to infiltrate to grain boundary. Alternatively, an anisotropic magnet can be fabricated by sintering Nd2Fe14B powder pre-aligned with a static magnetic field. In this study, we used a two-step electromagnetic vibration (EMV) technique to solidify the Nd70Cu30-30wt% Nd2Fe14B alloy, by which the magnetic Nd2Fe14B compound could be segmented into short laths and the easy magnetisation axes of these discontinuous platelets could be highly aligned, as revealed by electron backscatter diffraction (EBSD) patterns. Magnetic properties showed that the alloy exhibited strong anisotropy in its magnetism. Our present results opened a new avenue for the simple production of anisotropic Nd2Fe14B magnets via solidification without the powder metallurgy routine. Moreover, the technique is highly expected to be applied to other systems, e.g., graphene-reinforced metallic and/or polymer composites in which the alignment of graphene can maximise the anisotropy in the thermal or electrical properties of the composites.
Tubulin is actively exported from the nucleus through the Exportin1/CRM1 pathway
Authors: Schwarzerová K. , Bellinvia E. , Martinek J. , Sikorová L. , Dostál V. , Libusová L. , Bokvaj P. , Fischer L. , Schmit A. C. , Nick P.
Published: April 2019

Microtubules of all eukaryotic cells are formed by α- and β-tubulin heterodimers. In addition to the well known cytoplasmic tubulins, a subpopulation of tubulin can occur in the nucleus. So far, the potential function of nuclear tubulin has remained elusive. In this work, we show that α- and β-tubulins of various organisms contain multiple conserved nuclear export sequences, which are potential targets of the Exportin 1/CRM1 pathway. We demonstrate exemplarily that these NES motifs are sufficient to mediate export of GFP as model cargo and that this export can be inhibited by leptomycin B, an inhibitor of the Exportin 1/CRM1 pathway. Likewise, leptomycin B causes accumulation of GFP-tagged tubulin in interphase nuclei, in both plant and animal model cells. Our analysis of nuclear tubulin content supports the hypothesis that an important function of nuclear tubulin export is the exclusion of tubulin from interphase nuclei, after being trapped by nuclear envelope reassembly during telophase.
A Tumor-Selective Monoclonal Antibody from Immunization with a Tumor-Associated Mucin Glycopeptide
Authors: Trabbic Kevin R. , Whalen Kaitlyn , Abarca-Heideman Karin , Xia Li , Temme J. Sebastian , Edmondson Elijah F. , Gildersleeve Jeffrey C. , Barchi Joseph J.
Published: April 2019

We have previously studied the generation of immune responses after vaccination with tumor-associated carbohydrate antigen (TACA)-containing glycopeptides from the tandem repeat (TR) sequence of MUC4, an aberrantly expressed mucin in pancreatic adenocarcinomas. A specific lead antigen from that study containing the Thomsen-Friedenreich TACA disaccharide facilitated the pursuit of a monoclonal antibody to this synthetic hapten. Initial evaluation of polyclonal antiserum resulting from immunization with a KLH conjugate of this glycopeptide into rabbits showed high titer antibodies by ELISA assays, and selective immunoreactivity with MUC4+ cells by western blot and flow cytometry techniques. Glycan microarray analysis showed an intriguing binding pattern where the antiserum showed near complete specificity for MUC4 TR glycopeptides and peptides, relative to all components on the array. Tissue staining also showed distinct tumor specificity to pancreatic tumor tissue in relation to normal pancreatic tissue, with a preference for more aggressive tumor foci. Based on this data, we produced a monoclonal antibody whose binding and reactivity profile was similar to that of the polyclonal serum, with the added benefit of being more specific for the N-terminal glycosylated peptide domain. This epitope represents a novel immunogen to potentially develop diagnostic antibodies or immunotherapies against various MUC4-positive cancers.
Tight N-observable uncertainty relations and their experimental demonstrations
Authors: Chen Zhi-Xin , Wang Hui , Li Jun-Li , Song Qiu-Cheng , Qiao Cong-Feng
Published: April 2019

The uncertainty relation, as one of the fundamental principles of quantum physics, captures the incompatibility of noncommuting observables in the preparation of quantum states. In this work, we derive two strong and universal uncertainty relations for N(N ≥ 2) observables with discrete and bounded spectra, one in multiplicative form and the other in additive form. To verify their validity, for illustration, we implement in the spin-1/2 system an experiment with single-photon measurement. The experimental results exhibit the validity and robustness of these uncertainty relations, and indicate the existence of stringent lower bounds.
A Comparison of Static and Dynamic Functional Connectivities for Identifying Subjects and Biological Sex Using Intrinsic Individual Brain Connectivity
Authors: Menon Sreevalsan S. , Krishnamurthy K.
Published: April 2019

Functional magnetic resonance imaging has revealed correlated activities in brain regions even in the absence of a task. Initial studies assumed this resting-state functional connectivity (FC) to be stationary in nature, but recent studies have modeled these activities as a dynamic network. Dynamic spatiotemporal models better model the brain activities, but are computationally more involved. A comparison of static and dynamic FCs was made to quantitatively study their efficacies in identifying intrinsic individual connectivity patterns using data from the Human Connectome Project. Results show that the intrinsic individual brain connectivity pattern can be used as a ‘fingerprint’ to distinguish among and identify subjects and is more accurately captured with partial correlation and assuming static FC. It was also seen that the intrinsic individual brain connectivity patterns were invariant over a few months. Additionally, biological sex identification was successfully performed using the intrinsic individual connectivity patterns, and group averages of male and female FC matrices. Edge consistency, edge variability and differential power measures were used to identify the major resting-state networks involved in identifying subjects and their sex.
Functional evaluation of PDGFB-variants in idiopathic basal ganglia calcification, using patient-derived iPS cells
Authors: Sekine Shin-ichiro , Kaneko Masayuki , Tanaka Masaki , Ninomiya Yuhei , Kurita Hisaka , Inden Masatoshi , Yamada Megumi , Hayashi Yuichi , Inuzuka Takashi , Mitsui Jun , Ishiura Hiroyuki , Iwata Atsushi , Fujigasaki Hiroto , Tamaki Hisamitsu , Tamaki Ryusei , Kito Shinsuke , Taguchi Yoshiharu , Tanaka Kortaro , Atsuta Naoki , Sobue Gen , Kondo Takayuki , Inoue Haruhisa , Tsuji Shoji , Hozumi Isao
Published: April 2019

Causative genes in patients with idiopathic basal ganglia calcification (IBGC) (also called primary familial brain calcification (PFBC)) have been reported in the past several years. In this study, we surveyed the clinical and neuroimaging data of 70 sporadic patients and 16 families (86 unrelated probands in total) in Japan, and studied variants of PDGFB gene in the patients. Variant analyses of PDGFB showed four novel pathogenic variants, namely, two splice site variants (c.160 + 2T > A and c.457−1G > T), one deletion variant (c.33_34delCT), and one insertion variant (c.342_343insG). Moreover, we developed iPS cells (iPSCs) from three patients with PDGFB variants (c.160 + 2T > A, c.457−1G > T, and c.33_34 delCT) and induced endothelial cells. Enzyme-linked immunoassay analysis showed that the levels of PDGF-BB, a homodimer of PDGF-B, in the blood sera of patients with PDGFB variants were significantly decreased to 34.0% of that of the control levels. Those in the culture media of the endothelial cells derived from iPSCs of patients also significantly decreased to 58.6% of the control levels. As the endothelial cells developed from iPSCs of the patients showed a phenotype of the disease, further studies using IBGC-specific iPSCs will give us more information on the pathophysiology and the therapy of IBGC in the future.
Longitudinal proliferation mapping in vivo reveals NADPH oxidase-mediated dampening of Staphylococcus aureus growth rates within neutrophils
Authors: Seiß Elena A. , Krone Anna , Formaglio Pauline , Goldmann Oliver , Engelmann Susanne , Schraven Burkhart , Medina Eva , Müller Andreas J.
Published: April 2019

Upon the onset of inflammatory responses, bacterial pathogens are confronted with altered tissue microenvironments which can critically impact on their metabolic activity and growth. Changes in these parameters have however remained difficult to analyze over time, which would be critical to dissect the interplay between the host immune response and pathogen physiology. Here, we established an in vivo biosensor for measuring the growth rates of Staphylococcus aureus (S. aureus) on a single cell-level over days in an ongoing cutaneous infection. Using intravital 2-photon imaging and quantitative fluorescence microscopy, we show that upon neutrophil recruitment to the infection site and bacterial uptake, non-lethal dampening of S. aureus proliferation occurred. This inhibition was supported by NADPH oxidase activity. Therefore, reactive oxygen production contributes to pathogen containment within neutrophils not only by killing S. aureus, but also by restricting the growth rate of the bacterium.
Evolution of folate biosynthesis and metabolism across algae and land plant lineages
Authors: Gorelova V. , Bastien O. , De Clerck O. , Lespinats S. , Rébeillé F. , Van Der Straeten D.
Published: April 2019

Tetrahydrofolate and its derivatives, commonly known as folates, are essential for almost all living organisms. Besides acting as one-carbon donors and acceptors in reactions producing various important biomolecules such as nucleic and amino acids, as well as pantothenate, they also supply one-carbon units for methylation reactions. Plants along with bacteria, yeast and fungi synthesize folates de novo and therefore constitute a very important dietary source of folates for animals. All the major steps of folate biosynthesis and metabolism have been identified but only few have been genetically characterized in a handful of model plant species. The possible differences in the folate pathway between various plant and algal species have never been explored. In this study we present a comprehensive comparative study of folate biosynthesis and metabolism of all major land plant lineages as well as green and red algae. The study identifies new features of plant folate metabolism that might open new directions to folate research in plants.
Acoustic tweezing cytometry for mechanical phenotyping of macrophages and mechanopharmaceutical cytotripsy
Authors: Hong Xiaowei , Rzeczycki Phillip M. , Keswani Rahul K. , Murashov Mikhail D. , Fan Zhenzhen , Deng Cheri X. , Rosania Gus R.
Published: April 2019

Macrophages are immune cells responsible for tissue debridement and fighting infection. Clofazimine, an FDA-approved antibiotic, accumulates and precipitates as rod-shaped, crystal-like drug inclusions within macrophage lysosomes. Drug treatment as well as pathophysiological states could induce changes in macrophage mechanical property which in turn impact their phenotype and function. Here we report the use of acoustic tweezing cytometry as a new approach for in situ mechanical phenotyping of macrophages and for targeted macrophage cytotripsy. Acoustic tweezing cytometry applies ultrasound pulses to exert controlled forces to individual cells via integrin-bound microbubbles, enabling a creep test for measuring cellular mechanical property or inducing irreversible changes to the cells. Our results revealed that macrophages with crystal-like drug inclusions became significantly softer with higher cell compliance, and behaved more elastic with faster creep and recovery time constants. On the contrary, phagocytosis of solid polyethylene microbeads or treatment with soluble clofazimine rendered macrophages stiffer. Most notably, application of ultrasound pulses of longer duration and higher amplitude in ATC actuated the integrin-bound microbubbles to mobilize the crystal-like drug inclusions inside macrophages, turning the rod-shaped drug inclusions into intracellular microblender that effectively destructed the cells. This phenomenon of acoustic mechanopharmaceutical cytotripsy may be exploited for ultrasound activated, macrophage-directed drug release and delivery.
Thermal transport across grain boundaries in polycrystalline silicene: A multiscale modeling
Authors: Khalkhali Maryam , Rajabpour Ali , Khoeini Farhad
Published: April 2019

During the fabrication process of large scale silicene, through common chemical vapor deposition (CVD) technique, polycrystalline films are quite likely to be produced, and the existence of Kapitza thermal resistance along grain boundaries could result in substantial changes of their thermal properties. In the present study, the thermal transport along polycrystalline silicene was evaluated by performing a multiscale method. Non-equilibrium molecular dynamics simulations (NEMD) was carried out to assess the interfacial thermal resistance of various constructed grain boundaries in silicene. The effects of tensile strain and the mean temperature on the interfacial thermal resistance were also examined. In the following stage, the effective thermal conductivity of polycrystalline silicene was investigated considering the effects of grain size and tensile strain. Our results indicate that the average values of Kapitza conductance at grain boundaries at room temperature were estimated to be nearly 2.56 × 109 W/m2 K and 2.46 × 109 W/m2 K through utilizing Tersoff and Stillinger-Weber interatomic potentials respectively. Also, in spite of the mean temperature, whose increment does not change Kapitza resistance, the interfacial thermal resistance could be controlled by applying strain. Furthermore, it was found that by tuning the grain size of polycrystalline silicene, its thermal conductivity could be modulated up to one order of magnitude.
Unravelling the genetic basis of Fusarium seedling rot resistance in the MAGIC maize population: novel targets for breeding
Authors: Septiani Popi , Lanubile Alessandra , Stagnati Lorenzo , Busconi Matteo , Nelissen Hilde , Pè Mario Enrico , Dell’Acqua Matteo , Marocco Adriano
Published: April 2019

Fungal infection by Fusarium verticillioides is cause of prevalent maize disease leading to substantial reductions in yield and grain quality worldwide. Maize resistance to the fungus may occur at different developmental stages, from seedling to maturity. The breeding of resistant maize genotypes may take advantage of the identification of quantitative trait loci (QTL) responsible for disease resistance already commenced at seedling level. The Multi-parent Advance Generation Intercross (MAGIC) population was used to conduct high-definition QTL mapping for Fusarium seedling rot (FSR) resistance using rolled towel assay. Infection severity level, seedling weight and length were measured on 401 MAGIC maize recombinant inbred lines (RILs). QTL mapping was performed on reconstructed RIL haplotypes. One-fifth of the MAGIC RILs were resistant to FSR and 10 QTL were identified. For FSR, two QTL were detected at 2.8 Mb and 241.8 Mb on chromosome 4, and one QTL at 169.6 Mb on chromosome 5. Transcriptomic and sequencing information generated on the MAGIC founder lines was used to guide the identification of eight candidate genes within the identified FSR QTL. We conclude that the rolled towel assay applied to the MAGIC maize population provides a fast and cost-effective method to identify QTL and candidate genes for early resistance to F. verticillioides in maize.