bluuebunny/crossref_metadata_2025 huggingface dataset:
A SQL to C compiler in 500 lines of code
Authors: ROMPF TIARK , AMIN NADA
Published: June 2019

We present the design and implementation of a SQL query processor that outperforms existing database systems and is written in just about 500 lines of Scala code – a convincing case study that high-level functional programming can handily beat C for systems-level programming where the last drop of performance matters. The key enabler is a shift in perspective toward generative programming. The core of the query engine is an interpreter for relational-algebra operations, written in Scala. Using the open-source lightweight modular staging framework, we turn this interpreter into a query compiler with very low effort. To do so, we capitalize on an old and widely known result from partial evaluation: the first Futamura projection, which states that a process that can specialize an interpreter to any given input program is equivalent to a compiler. In this context, we discuss lightweight modular staging programming patterns such as mixed-stage data structures (e.g., data records with static schema and dynamic field components) and techniques to generate low-level C code, including specialized data structures and data loading primitives.
Penitential Manuscripts and the Teaching of Penance in Carolingian Europe
Authors: Leontidou Eleni
Published: June 2019

This article discusses the educational value of penitential literature in Carolingian Francia. In particular, it looks at manuscripts which were not simple penitential handbooks but were compiled as educational tools for priests. Apart from penitential works, these manuscripts included monastic rules, moral and ascetic works providing moral instruction, and, in some cases, school texts and glossaries.
Peter Canisius and the Development of Catholic Education in Germany, 1549–97
Authors: Atherton Ruth
Published: June 2019

The Jesuit Peter Canisius (1521–97) became widely respected as a catechist, pedagogue and preacher who worked tirelessly on behalf of the Catholic faith. Canisius's set of three catechisms – theLarge,SmallandSmaller– were the most popular and widely available Catholic catechisms in sixteenth-century Germany: by his death, at least 357 editions had appeared, in a number of languages. Employed in Catholic schools, churches and homes across the Holy Roman Empire, his catechisms have been interpreted as a direct response to the Protestant attack on Catholicism in Germany. However, the boundaries between Catholicism and heresy were not always clear to the laity. Drawing on examples from his catechisms and his approach to the Index of Prohibited Books, this article suggests that Canisius sought to promote a policy of inclusion among his fellow Catholics in a time of conflict and uncertainty. In recognizing the distinct nature of German Catholicism, Canisius advocated a tailored educational approach to contentious doctrines and practices. Directed towards the German laity, this approach taught the lesson of compromise and acceptance among those who identified as Catholic. The article adds to existing scholarship on Jesuit education, Canisius's contribution to the development of a German religious identity, Jesuit casuistry and the dissemination of religious knowledge in German society.
‘War to the knife’? The Anglican Clergy and Education at the End of the First World War
Authors: Smith Mark
Published: June 2019

In 1918 Charles Gore, the bishop of Oxford, issued queries preparatory to an episcopal visitation, including a series of questions about the future of church schools and religious education more generally. Coming some sixteen years after the restructuring of the dual system of state- and church-supported education by the Balfour Education Act of 1902, this material yields valuable insights into the views of approximately six hundred clergy regarding the successes and dysfunctions of the system at parish level. Set within the context of recent historiography on the trajectory of English Christianity in the1920s, this article uses this material to discuss the clergy's views on the value and purposes of school-based religious education, the prospects for sustaining these after almost four years of war and the compromises that might be required in order to preserve them.
Convent Schooling for English Girls in the ‘Exile’ Period, 1600–1800
Authors: Bowden Caroline
Published: June 2019

Following the Reformation, Catholic families seeking to educate both sons and daughters in their faith faced many challenges. The penal laws proscribed the creation of Catholic schools in England and forbade parents to send children abroad for education. However, such was the determination to provide Catholic schooling that families were prepared to break the laws and meet the expense of fees and travel. The convents established schools for several reasons. For some orders it was part of their religious purpose to educate girls, others saw it as a means of educating future members, and all needed to secure their convents financially and be self-sufficient. Schooling provided varied significantly. This article, drawing mainly on manuscript sources from convents and some of the families with daughters attending convent schools, considers the scope of the provision of girls' education in the ‘exile’ period and offers some preliminary insights into the experience of pupils.
Danish Catechism in Action? Examining Religious Formation in and through Erik Pontoppidan'sMenoza
Authors: Lied Laurel
Published: June 2019

In 1737 Erik Pontoppidan, a Danish bishop of pietist leanings, published a Lutheran catechism,Sandhed til Gudfrygtighed(Truth unto Godliness), which became the Church of Denmark's official catechism for the following fifty years, with new editions being printed in Norway into the twentieth century. For a figure largely overlooked by modern scholarship, he has enjoyed an extraordinarily lengthy influence over Christian formation in Scandinavia and in Norwegian immigrant communities in the USA. Pontoppidan not only left behind this ‘official’ programme of Christian education, but also an unofficial blueprint,Menoza(1742–3). Thisopbyggelse(‘edifying’) novel recounts the conversion of an imaginary Indian prince, Menoza, and his subsequent travels around Europe.Menozamight even be said to offer its readers an alternative or additional Lutheran catechism in literary form. This article examines Menoza's Christian formation in the light of Pontoppidan's official catechism. Which topics of the catechism receive emphasis or are downplayed? Does the progression and linking of doctrinal topics match the catechism's layout or does the author restructure Christian theology for pedagogical purposes? The article also considers the non-doctrinal elements of the characters’ catechesis, especially in relation to pietist expectations regarding conversion. What indoctrination, intentional or unintentional, into the vocabulary and experience of pietist culture did Pontoppidan offer his Scandinavian readers?
Saving Souls on a Shoestring: Welsh Circulating Schools in a Century of Change
Authors: Yates Paula
Published: June 2019

This article examines the phenomenon of Welsh circulating schools from those of Griffith Jones in the mid-eighteenth century, which over nearly fifty years brought the basics of religious education to thousands of poor children and adults, to their successors later in the century under Thomas Charles and, in the nineteenth century, the Bevan Charity. It compares Jones's success with the relatively limited impact of the later schemes and seeks to demonstrate the importance of his flair for publicity, his connections, his use of Anglican networks and his organizational ability. The article considers how the changed political and social climate in the last decades of the eighteenth century and into the nineteenth affected the success of later schemes and describes how the schools had to adapt to changed expectations and new educational developments. It argues that the schools provide strong evidence against the view that the charity school movement was motivated primarily by the desire for social control.
‘In perfect harmony with the spirit of the age’: The Oxford University Wesley Guild, 1883–1914
Authors: Wellings Martin
Published: June 2019

From the middle of the nineteenth century, educational opportunities at the older English universities were gradually extended beyond the limits of the Church of England, first with the abolition of the university tests and then with the opening of higher degrees to Nonconformists. Wesleyan Methodists were keen to take advantage of this new situation, and also to safeguard their young people from non-Methodist influences. A student organization was established in Oxford in 1883, closely linked to the city centre chapel and its ministers, and this Wesley Guild (later the Wesley Society, and then the John Wesley Society) formed the heart of Methodist involvement with the university's undergraduates for the next century. The article explores the background to the guild and its development in the years up to the First World War, using it as a case study for the engagement of Methodism with higher education in this period.
Conversion and Curriculum: Nonconformist Missionaries and the British and Foreign School Society in the British West Indies, Africa and India, 1800–50
Authors: Dornan Inge
Published: June 2019

This article examines the ways in which Nonconformist missionary societies worked hand in hand with the British and Foreign School Society (BFSS) to provide them with pedagogic training in the British System and BFSS teaching manuals and resources, as part of their evangelical mission of conversion in the British West Indies, Africa and India in the nineteenth century. The BFSS appealed to Nonconformist missionaries because it was based on unsectarian pedagogy, pioneered by the educationalist Joseph Lancaster. The article explores the various obstacles these missionaries faced, including the religious persecution they experienced in teaching an unsectarian system and the educational difficulties they experienced in persuading parents and local governments of the value of elementary education. It also draws attention to the ways in which they fought race and sex prejudice in the teaching of Africans, slaves and young girls. The current literature on missionary activities in the early nineteenth century pays scant attention to their role as educators: the article reveals the degree of their educational ambition and zeal and the lengths they went to in order to implement a progressive system of unsectarian elementary instruction in key parts of the British empire during the nineteenth century.
The Rise, Success and Dismantling of New Zealand's Anglican-led Māori Education System, 1814–64
Authors: Moon Paul
Published: June 2019

Anglican missionaries, serving under the auspices of the Church Missionary Society (CMS), were the first Europeans to settle in New Zealand. Within months of arriving in the country in 1814, they began to convert the language of the indigenous Māori into a written form in order to produce religious texts that would assist with Māori education and conversion. The CMS missionaries also established schools for Māori which later grew into a de facto state education system until the colonial government accelerated its plans for a secular school regime from the mid-1840s. Despite the sometimes awkward religious and cultural entanglements that accompanied missionary proselytizing in this era, the mission schools established by the CMS flourished in the succeeding decades, elevating Māori literacy levels and serving as a highly effective tool of Anglican evangelization. This article traces the arc of the CMS mission schools from their inception in 1814 to their demise in the early 1860s, a period during which the British, and later New Zealand, government's stance towards the mission schools went from ambivalence, through assistance, to antipathy.
Cassini's Final Year at Saturn: Science Highlights and Discoveries
Authors: Spilker Linda J.
Published: June 2019

Scientific findings and new discoveries from the international Cassini‐Huygens mission's exploration of the Saturn system are presented in this special issue of Geophysical Research Letters. In the mission's final year, Cassini dove through the gap between the rings and Saturn for the first time, returning new science in this previously unexplored region. Running low on fuel, Cassini's journey ended on 15 September 2017, as the spacecraft plunged into Saturn's atmosphere and vaporized. Just before the mission concluded, the Grand Finale orbits through the gap provided some of the highest resolution information on Saturn's interior and atmosphere, its rings and inner icy moons, and direct in situ sampling of this intriguing region. Initial results indicate that hydrocarbons appear to be descending into the atmosphere from the rings, that electric currents flow between the inner rings and Saturn, and that a new radiation belt exists in the gap and innermost ring.
Resolution and Ergodicity Issues of River Stage Tomography With Different Excitations
Authors: Wang Yu‐Li , Yeh Tian‐Chyi Jim , Wen Jet‐Chau , Gao Xu , Zhang Zaiyong , Huang Shao‐Yang
Published: June 2019

This study investigates spatiotemporal cross correlation between the observed head and the hydraulic diffusivity parameters in heterogeneous aquifers under static and migrating periodic excitations with different frequencies and other factors and a moving single excitation along a river boundary. Results of the cross‐correlation analysis are verified by estimating the parameters in a synthetic heterogeneous aquifer under these excitations. For assuring the statistical significance of the results based on a single realization, Monte Carlo experiments of estimating the parameters with these excitations are conducted. The experiments also explore the relationship between the resolution of the estimated parameters and the distance from the excitation to the observation wells, the frequency, and amplitude of the excitation and the mean diffusivity of the aquifer. In addition, the relationship between the resolution of the estimates and monitoring network spatial density is investigated. Finally, the usefulness of moving single excitations, effects of frequencies of the periodic excitations under different situations, the density of monitoring network in term of correlation scale, and the ergodicity issue corresponding to the number of observation and size of simulation domain are discussed.
Reaction injection molding of hydrophilic-in-hydrophobic femtolitre-well arrays
Authors: Zandi Shafagh Reza , Decrop Deborah , Ven Karen , Vanderbeke Arno , Hanusa Robert , Breukers Jolien , Pardon Gaspard , Haraldsson Tommy , Lammertyn Jeroen , van der Wijngaart Wouter
Published: June 2019

Patterning of micro- and nanoscale topologies and surface properties of polymer devices is of particular importance for a broad range of life science applications, including cell-adhesion assays and highly sensitive bioassays. The manufacturing of such devices necessitates cumbersome multiple-step fabrication procedures and results in surface properties which degrade over time. This critically hinders their wide-spread dissemination. Here, we simultaneously mold and surface energy pattern microstructures in off-stoichiometric thiol-ene by area-selective monomer self-assembly in a rapid micro-reaction injection molding cycle. We replicated arrays of 1,843,650 hydrophilic-in-hydrophobic femtolitre-wells with long-term stable surface properties and magnetically trapped beads with 75% and 87.2% efficiency in single- and multiple-seeding events, respectively. These results form the basis for ultrasensitive digital biosensors, specifically, and for the fabrication of medical devices and life science research tools, generally.
Familial risk and heritability of diagnosed borderline personality disorder: a register study of the Swedish population
Authors: Skoglund Charlotte , Tiger Annika , Rück Christian , Petrovic Predrag , Asherson Philip , Hellner Clara , Mataix-Cols David , Kuja-Halkola Ralf
Published: June 2019

Family and twin studies of Borderline Personality Disorder (BPD) have found familial aggregation and genetic propensity for BPD, but estimates vary widely. Large-scale family studies of clinically diagnosed BPD are lacking. Therefore, we performed a total-population study estimating the familial aggregation and heritability of clinically diagnosed BPD. We followed 1,851,755 individuals born 1973–1993 in linked Swedish national registries. BPD-diagnosis was ascertained between 1997 and 2013, 11,665 received a BPD-diagnosis. We identified relatives and estimated sex and birth year adjusted hazard ratios, i.e., the rate of BPD-diagnoses in relatives to individuals with BPD-diagnosis compared to individuals with unaffected relatives, and used structural equation modeling to estimate heritability. The familial association decreased along with genetic relatedness. The hazard ratio was 11.5 (95% confidence interval (CI) = 1.6–83.8) for monozygotic twins; 7.4 (95% CI = 1.0–55.3) for dizygotic twins; 4.7 (95% CI = 3.9–5.6) for full siblings; 2.1 (95% CI = 1.5–3.0) for maternal half-siblings; 1.3 (95% CI = 0.9–2.1) for paternal half-siblings; 1.7 (95% CI = 1.4–2.0) for cousins whose parents were full siblings; 1.1 (95% CI = 0.7–1.8) for cousins whose parents were maternal half-siblings; and 1.9 (95% CI = 1.2–2.9) for cousins whose parents were paternal half-siblings. Heritability was estimated at 46% (95% CI = 39–53), and the remaining variance was explained by individually unique environmental factors. Our findings pave the way for further research into specific genetic variants, unique environmental factors implicated, and their interplay in risk for BPD.
Neuroimaging-based brain-age prediction in diverse forms of epilepsy: a signature of psychosis and beyond
Authors: Sone Daichi , Beheshti Iman , Maikusa Norihide , Ota Miho , Kimura Yukio , Sato Noriko , Koepp Matthias , Matsuda Hiroshi
Published: June 2019

Epilepsy is a diverse brain disorder, and the pathophysiology of its various forms and comorbidities is largely unknown. A recent machine learning method enables us to estimate an individual’s “brain-age” from MRI; this brain-age prediction is expected as a novel individual biomarker of neuropsychiatric disorders. The aims of this study were to estimate the brain-age for various categories of epilepsy and to evaluate clinical discrimination by brain-age for (1) the effect of psychosis on temporal lobe epilepsy (TLE), (2) psychogenic nonepileptic seizures (PNESs) from MRI-negative epilepsies, and (3) progressive myoclonic epilepsy (PME) from juvenile myoclonic epilepsy (JME). In total, 1196 T1-weighted MRI scans from healthy controls (HCs) were used to build a brain-age prediction model with support vector regression. Using the model, we calculated the brain-predicted age difference (brain-PAD: predicted age—chronological age) of the HCs and 318 patients with epilepsy. We compared the brain-PAD values based on the research questions. As a result, all categories of patients except for extra-temporal lobe focal epilepsy showed a significant increase in brain-PAD. TLE with hippocampal sclerosis presented a significantly higher brain-PAD than several other categories. The mean brain-PAD in TLE with inter-ictal psychosis was 10.9 years, which was significantly higher than TLE without psychosis (5.3 years). PNES showed a comparable mean brain-PAD (10.6 years) to that of epilepsy patients. PME had a higher brain-PAD than JME (22.0 vs. 9.3 years). In conclusion, neuroimaging-based brain-age prediction can provide novel insight into or clinical usefulness for the diverse symptoms of epilepsy.
Activated Peyer′s patch B cells sample antigen directly from M cells in the subepithelial dome
Authors: Komban Rathan Joy , Strömberg Anneli , Biram Adi , Cervin Jakob , Lebrero-Fernández Cristina , Mabbott Neil , Yrlid Ulf , Shulman Ziv , Bemark Mats , Lycke Nils
Published: June 2019

The germinal center (GC) reaction in Peyer′s patches (PP) requires continuous access to antigens, but how this is achieved is not known. Here we show that activated antigen-specific CCR6+CCR1+GL7−B cells make close contact with M cells in the subepithelial dome (SED). Using in situ photoactivation analysis of antigen-specific SED B cells, we find migration of cells towards the GC. Following antigen injection into ligated intestinal loops containing PPs, 40% of antigen-specific SED B cells bind antigen within 2 h, whereas unspecifc cells do not, indicating B cell-receptor involvment. Antigen-loading is not observed in M cell-deficient mice, but is unperturbed in mice depleted of classical dendritic cells (DC). Thus, we report a M cell-B cell antigen-specific transporting pathway in PP that is independent of DC. We propose that this antigen transporting pathway has a critical role in gut IgA responses, and should be taken into account when developing mucosal vaccines.
Terminator-free template-independent enzymatic DNA synthesis for digital information storage
Authors: Lee Henry H. , Kalhor Reza , Goela Naveen , Bolot Jean , Church George M.
Published: June 2019

DNA is an emerging medium for digital data and its adoption can be accelerated by synthesis processes specialized for storage applications. Here, we describe a de novo enzymatic synthesis strategy designed for data storage which harnesses the template-independent polymerase terminal deoxynucleotidyl transferase (TdT) in kinetically controlled conditions. Information is stored in transitions between non-identical nucleotides of DNA strands. To produce strands representing user-defined content, nucleotide substrates are added iteratively, yielding short homopolymeric extensions whose lengths are controlled by apyrase-mediated substrate degradation. With this scheme, we synthesize DNA strands carrying 144 bits, including addressing, and demonstrate retrieval with streaming nanopore sequencing. We further devise a digital codec to reduce requirements for synthesis accuracy and sequencing coverage, and experimentally show robust data retrieval from imperfectly synthesized strands. This work provides distributive enzymatic synthesis and information-theoretic approaches to advance digital information storage in DNA.
Neural mechanisms of contextual modulation in the retinal direction selective circuit
Authors: Huang Xiaolin , Rangel Melissa , Briggman Kevin L. , Wei Wei
Published: June 2019

Contextual modulation of neuronal responses by surrounding environments is a fundamental attribute of sensory processing. In the mammalian retina, responses of On–Off direction selective ganglion cells (DSGCs) are modulated by motion contexts. However, the underlying mechanisms are unknown. Here, we show that posterior-preferring DSGCs (pDSGCs) are sensitive to discontinuities of moving contours owing to contextually modulated cholinergic excitation from starburst amacrine cells (SACs). Using a combination of synapse-specific genetic manipulations, patch clamp electrophysiology and connectomic analysis, we identified distinct circuit motifs upstream of On and Off SACs that are required for the contextual modulation of pDSGC activity for bright and dark contrasts. Furthermore, our results reveal a class of wide-field amacrine cells (WACs) with straight, unbranching dendrites that function as “continuity detectors” of moving contours. Therefore, divergent circuit motifs in the On and Off pathways extend the information encoding of On-Off DSGCs beyond their direction selectivity during complex stimuli.
Tau binding protein CAPON induces tau aggregation and neurodegeneration
Authors: Hashimoto Shoko , Matsuba Yukio , Kamano Naoko , Mihira Naomi , Sahara Naruhiko , Takano Jiro , Muramatsu Shin-ichi , Saido Takaomi C. , Saito Takashi
Published: June 2019

To understand the molecular processes that link Aβ amyloidosis, tauopathy and neurodegeneration, we screened for tau-interacting proteins by immunoprecipitation/LC-MS. We identified the carboxy-terminal PDZ ligand of nNOS (CAPON) as a novel tau-binding protein. CAPON is an adaptor protein of neuronal nitric oxide synthase (nNOS), and activated by the N-methyl-D-aspartate receptor. We observed accumulation of CAPON in the hippocampal pyramidal cell layer in the AppNL-G-F -knock-in (KI) brain. To investigate the effect of CAPON accumulation on Alzheimer’s disease (AD) pathogenesis, CAPON was overexpressed in the brain of AppNL-G-F mice crossbred with MAPT (human tau)-KI mice. This produced significant hippocampal atrophy and caspase3-dependent neuronal cell death in the CAPON-expressing hippocampus, suggesting that CAPON accumulation increases neurodegeneration. CAPON expression also induced significantly higher levels of phosphorylated, oligomerized and insoluble tau. In contrast, CAPON deficiency ameliorated the AD-related pathological phenotypes in tauopathy model. These findings suggest that CAPON could be a druggable AD target.
Listeners form average-based representations of individual voice identities
Authors: Lavan Nadine , Knight Sarah , McGettigan Carolyn
Published: June 2019

Models of voice perception propose that identities are encoded relative to an abstracted average or prototype. While there is some evidence for norm-based coding when learning to discriminate different voices, little is known about how the representation of an individual's voice identity is formed through variable exposure to that voice. In two experiments, we show evidence that participants form abstracted representations of individual voice identities based on averages, despite having never been exposed to these averages during learning. We created 3 perceptually distinct voice identities, fully controlling their within-person variability. Listeners first learned to recognise these identities based on ring-shaped distributions located around the perimeter of within-person voice spaces – crucially, these distributions were missing their centres. At test, listeners’ accuracy for old/new judgements was higher for stimuli located on an untrained distribution nested around the centre of each ring-shaped distribution compared to stimuli on the trained ring-shaped distribution.
Augmented manipulation ability in humans with six-fingered hands
Authors: Mehring C. , Akselrod M. , Bashford L. , Mace M. , Choi H. , Blüher M. , Buschhoff A.-S. , Pistohl T. , Salomon R. , Cheah A. , Blanke O. , Serino A. , Burdet E.
Published: June 2019

Neurotechnology attempts to develop supernumerary limbs, but can the human brain deal with the complexity to control an extra limb and yield advantages from it? Here, we analyzed the neuromechanics and manipulation abilities of two polydactyly subjects who each possess six fingers on their hands. Anatomical MRI of the supernumerary finger (SF) revealed that it is actuated by extra muscles and nerves, and fMRI identified a distinct cortical representation of the SF. In both subjects, the SF was able to move independently from the other fingers. Polydactyly subjects were able to coordinate the SF with their other fingers for more complex movements than five fingered subjects, and so carry out with only one hand tasks normally requiring two hands. These results demonstrate that a body with significantly more degrees-of-freedom can be controlled by the human nervous system without causing motor deficits or impairments and can instead provide superior manipulation abilities.
A corner reflector of graphene Dirac fermions as a phonon-scattering sensor
Authors: Graef H. , Wilmart Q. , Rosticher M. , Mele D. , Banszerus L. , Stampfer C. , Taniguchi T. , Watanabe K. , Berroir J.-M. , Bocquillon E. , Fève G. , Teo E. H. T. , Plaçais B.
Published: June 2019

Dirac fermion optics exploits the refraction of chiral fermions across optics-inspired Klein-tunneling barriers defined by high-transparency p-n junctions. We consider the corner reflector (CR) geometry introduced in optics or radars. We fabricate Dirac fermion CRs using bottom-gate-defined barriers in hBN-encapsulated graphene. By suppressing transmission upon multiple internal reflections, CRs are sensitive to minute phonon scattering rates. Here we report on doping-independent CR transmission in quantitative agreement with a simple scattering model including thermal phonon scattering. As a signature of CRs, we observe Fabry-Pérot oscillations at low temperature, consistent with single-path reflections. Finally, we demonstrate high-frequency operation which promotes CRs as fast phonon detectors. Our work establishes the relevance of Dirac fermion optics in graphene and opens a route for its implementation in topological Dirac matter.
Low-energy electrons transform the nimorazole molecule into a radiosensitiser
Authors: Meißner Rebecca , Kočišek Jaroslav , Feketeová Linda , Fedor Juraj , Fárník Michal , Limão-Vieira Paulo , Illenberger Eugen , Denifl Stephan
Published: June 2019

While matter is irradiated with highly-energetic particles, it may become chemically modified. Thereby, the reactions of free low-energy electrons (LEEs) formed as secondary particles play an important role. It is unknown to what degree and by which mechanism LEEs contribute to the action of electron-affinic radiosensitisers applied in radiotherapy of hypoxic tumours. Here we show that LEEs effectively cause the reduction of the radiosensitiser nimorazole via associative electron attachment with the cross-section exceeding most of known molecules. This supports the hypothesis that nimorazole is selectively cytotoxic to tumour cells due to reduction of the molecule as prerequisite for accumulation in the cell. In contrast, dissociative electron attachment, commonly believed to be the source of chemical activity of LEEs, represents only a minor reaction channel which is further suppressed upon hydration. Our results show that LEEs may strongly contribute to the radiosensitising effect of nimorazole via associative electron attachment.
Extracellular vesicles from CLEC2-activated platelets enhance dengue virus-induced lethality via CLEC5A/TLR2
Authors: Sung Pei-Shan , Huang Tur-Fu , Hsieh Shie-Liang
Published: June 2019

Platelet-leukocyte interactions amplify inflammatory reactions, but the underlying mechanism is still unclear. CLEC5A and CLEC2 are spleen tyrosine kinase (Syk)-coupled C-type lectin receptors, abundantly expressed by leukocytes and platelets, respectively. Whereas CLEC5A is a pattern recognition receptor (PRR) to flaviviruses and bacteria, CLEC2 is the receptor for platelet-activating snake venom aggretin. Here we show that dengue virus (DV) activates platelets via CLEC2 to release extracellular vesicles (EVs), including exosomes (EXOs) and microvesicles (MVs). DV-induced EXOs (DV-EXOs) and MVs (DV-MVs) further activate CLEC5A and TLR2 on neutrophils and macrophages, thereby induce neutrophil extracellular trap (NET) formation and proinflammatory cytokine release. Compared to  stat1−/− mice, simultaneous blockade of CLEC5A and TLR2 effectively attenuates DV-induced inflammatory response and increases survival rate from 30 to 90%. The identification of critical roles of CLEC2 and CLEC5A/TLR2 in platelet-leukocyte interactions will support the development of novel strategies to treat acute viral infection in the future.
Structures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutations
Authors: Birkinshaw Richard W. , Gong Jia-nan , Luo Cindy S. , Lio Daisy , White Christine A. , Anderson Mary Ann , Blombery Piers , Lessene Guillaume , Majewski Ian J. , Thijssen Rachel , Roberts Andrew W. , Huang David C. S. , Colman Peter M. , Czabotar Peter E.
Published: June 2019

Venetoclax is a first-in-class cancer therapy that interacts with the cellular apoptotic machinery promoting apoptosis. Treatment of patients suffering chronic lymphocytic leukaemia with this BCL-2 antagonist has revealed emergence of a drug-selected BCL-2 mutation (G101V) in some patients failing therapy. To understand the molecular basis of this acquired resistance we describe the crystal structures of venetoclax bound to both BCL-2 and the G101V mutant. The pose of venetoclax in its binding site on BCL-2 reveals small but unexpected differences as compared to published structures of complexes with venetoclax analogues. The G101V mutant complex structure and mutant binding assays reveal that resistance is acquired by a knock-on effect of V101 on an adjacent residue, E152, with venetoclax binding restored by a E152A mutation. This provides a framework for considering analogues of venetoclax that might be effective in combating this mutation.
Single particle cryo-EM reconstruction of 52 kDa streptavidin at 3.2 Angstrom resolution
Authors: Fan Xiao , Wang Jia , Zhang Xing , Yang Zi , Zhang Jin-Can , Zhao Lingyun , Peng Hai-Lin , Lei Jianlin , Wang Hong-Wei
Published: June 2019

The fast development of single-particle cryogenic electron microscopy (cryo-EM) has made it more feasible to obtain the 3D structure of well-behaved macromolecules with a molecular weight higher than 300 kDa at ~3 Å resolution. However, it remains a challenge to obtain the high-resolution structures of molecules smaller than 200 kDa using single-particle cryo-EM. In this work, we apply the Cs-corrector-VPP-coupled cryo-EM to study the 52 kDa streptavidin (SA) protein supported on a thin layer of graphene and embedded in vitreous ice. We are able to solve both the apo-SA and biotin-bound SA structures at near-atomic resolution using single-particle cryo-EM. We demonstrate that the method has the potential to determine the structures of molecules as small as 39 kDa.
Feed-forward regulation adaptively evolves via dynamics rather than topology when there is intrinsic noise
Authors: Xiong Kun , Lancaster Alex K. , Siegal Mark L. , Masel Joanna
Published: June 2019

In transcriptional regulatory networks (TRNs), a canonical 3-node feed-forward loop (FFL) is hypothesized to evolve to filter out short spurious signals. We test this adaptive hypothesis against a novel null evolutionary model. Our mutational model captures the intrinsically high prevalence of weak affinity transcription factor binding sites. We also capture stochasticity and delays in gene expression that distort external signals and intrinsically generate noise. Functional FFLs evolve readily under selection for the hypothesized function but not in negative controls. Interestingly, a 4-node “diamond” motif also emerges as a short spurious signal filter. The diamond uses expression dynamics rather than path length to provide fast and slow pathways. When there is no idealized external spurious signal to filter out, but only internally generated noise, only the diamond and not the FFL evolves. While our results support the adaptive hypothesis, we also show that non-adaptive factors, including the intrinsic expression dynamics, matter.
Room temperature terahertz semiconductor frequency comb
Authors: Lu Quanyong , Wang Feihu , Wu Donghai , Slivken Steven , Razeghi Manijeh
Published: June 2019

A terahertz (THz) frequency comb capable of high-resolution measurement will significantly advance THz technology application in spectroscopy, metrology and sensing. The recently developed cryogenic-cooled THz quantum cascade laser (QCL) comb has exhibited great potentials with high power and broadband spectrum. Here, we report a room temperature THz harmonic frequency comb in 2.2 to 3.3 THz based on difference-frequency generation from a mid-IR QCL. The THz comb is intracavity generated via down-converting a mid-IR comb with an integrated mid-IR single mode based on distributed-feedback grating without using external optical elements. The grating Bragg wavelength is largely detuned from the gain peak to suppress the grating dispersion and support the comb operation in the high gain spectral range. Multiheterodyne spectroscopy with multiple equally spaced lines by beating it with a reference Fabry-Pérot comb confirms the THz comb operation. This type of THz comb will find applications to room temperature chip-based THz spectroscopy.
Posterior samples of the parameters of binary black holes from Advanced LIGO, Virgo’s second observing run
Authors: De Soumi , Biwer Christopher M. , Capano Collin D. , Nitz Alexander H. , Brown Duncan A.
Published: June 2019

This paper presents a parameter estimation analysis of the seven binary black hole mergers—GW170104, GW170608, GW170729, GW170809, GW170814, GW170818, and GW170823—detected during the second observing run of the Advanced LIGO and Virgo observatories using the gravitational-wave open data. We describe the methodology for parameter estimation of compact binaries using gravitational-wave data, and we present the posterior distributions of the inferred astrophysical parameters. We release our samples of the posterior probability density function with tutorials on using and replicating our results presented in this paper.
M. tuberculosis infection and antigen specific cytokine response in healthcare workers frequently exposed to tuberculosis
Authors: Essone Paulin N. , Leboueny Marielle , Maloupazoa Siawaya Anicet Christel , Alame-Emane Amel Kévin , Aboumegone Biyogo Oriane Cordelia , Dapnet Tadatsin Patrice Hemery , Mveang Nzoghe Amandine , Essamazokou Dimitri Ulrich , Mvoundza Ndjindji Ofilia , Padzys Guy-Stéphane , Agnandji Selidji Todagbe , Takiff Howard , Gicquel Brigitte , Djoba Siawaya Joel Fleury
Published: June 2019

Tuberculosis (TB) is the leading cause of death due to an infectious agent, but only a small fraction of those infected develop the disease. Cytokines are involved in the mediation and regulation of immunity, and their secretion patterns may reflect the infection status. To increase our understanding of immune response toM.tuberculosisinfection, we conducted a cross-sectional study investigatingM.tuberculosisinfection status and comparing the release profiles of cytokines GM-CSF, IFN-γ, IL-1β, IL-10, IL-12 (p70), IL-2, IL-4, IL-5, IL-6, IL-8, TNF-α, in community controls (CCs) and healthy healthcare workers (HCWs) highly exposed to TB. Among HCWs and CCs, the probability of latentM.tuberculosis(LTB+) infection was respectively 5.4 (p = 0.002) and 3.4 (p = 0.006) times higher in men than women. The odds ratio of LTB infection was 4 times higher among HCWs in direct contact with active TB patients than other HCW (p = 0.01). Whole blood supernatant cytokine responses toM.tuberculosisantigens showed differential pro-inflammatory responses between HCWs and CCs. CCsLTB−had higher IL-1β responses than HCWsLTB−(p = 0.002). HCWsLTB+had significantly higher IL-8 responses toM.tuberculosisantigens than HCWsLTB−(p = 0.003) and CCsLTB−(p = 0.015). HCWsLTB+/−showed weak but positive TNF-α responses toM.tuberculosisantigen stimulation compared to CCsLTB+/−(p ≤ 0.015). Looking at T-helper (1 and 2) responses, HCWsLTB+and CCsLTB+had significantly higher IFN-γ and IL-2 responses compared to HCWsLTB−and CCsLTB−(p < [0.0001–0.003]). Also, TB antigen induced IL-5 secretion was significantly higher in HCWsLTB+and CCsLTB+than in non-infected CCsLTB−(p < [0.005–0.04]).M.tuberculosisantigen specific responses in HCWsLTB+varied based on active TB exposure gradient. HCWsLTB+who were highly exposed to active TB (≥3 hours per day) had significantly higher IFN-γ and IL-8 responses (p ≤ 0.02) than HCWsLTB+not in direct contact with active TB patients. HCWsLTB+working with active TB patients for 5 to 31 years had a significantly enhanced secretion of proinflammatory cytokines (GM-CSF, IFN-γ, IL-1β, IL-2, IL-6, IL-8, IL-12p70, TNF-α) compared to HCWsLTB−(p < [0.0001–0.01]). Secretion of anti-inflammatory/Th2 cytokines IL-5 and IL-10 was also higher in HCWsLTB+than HCWsLTB−. In conclusion, LTBI individuals controlling theM.tuberculosisinfection have an enhanced TB specific Th1-cytokines/proinflammatory response combined with selected Th2 type/anti-inflammatory cytokines induction.
The association between physical activity and low back pain: a systematic review and meta-analysis of observational studies
Authors: Alzahrani Hosam , Mackey Martin , Stamatakis Emmanuel , Zadro Joshua Robert , Shirley Debra
Published: June 2019

The aim of this review was to investigate the association between total and domain-specific physical activity (PA) and non-specific low back pain (LBP) in adults. Seven databases were searched for cohort and cross-sectional studies. Pooled estimates of the association of medium and high levels PA and LBP, using the generic inverse-variance method with fixed- and random-effects models were calculated. Twenty-four studies (15 cohort and nine cross-sectional; 95,796 participants) were included. The pooled fully adjusted risk ratios (RR) from cohort studies comparing medium with lowest activity levels were 0.90 (95%CI 0.85 to 0.96) for total PA, and 0.90 (95%CI 0.85 to 0.96) for leisure-time PA (LTPA). The pooled RR comparing highest with lowest activity levels were 1.00 (95%CI 0.92 to 1.08) for total PA, and 1.01 (95%CI 0.93 to 1.10) for LTPA. The pooled fully adjusted odds ratios (OR) from cross-sectional studies comparing medium with lowest activity levels were 0.93 (95%CI 0.65 to 1.32) for total PA, and 0.77 (95%CI 0.62 to 0.96) for LTPA. The pooled OR comparing highest with lowest activity levels were 1.05 (95%CI 0.89 to 1.23) for total PA, and 0.85 (95%CI 0.79 to 0.93) for LTPA. PA seems to be associated with lower prevalence of LBP.
Social and Physiological Context can Affect the Meaning of Physiological Synchrony
Authors: Danyluck Chad , Page-Gould Elizabeth
Published: June 2019

Survival of many species, from insects and birds to human and non-human mammals, requires synchronized activity. Among humans, synchrony occurs even at the level of autonomic functioning; people interacting often show mutual, simultaneous changes in activity of the sympathetic or parasympathetic branches of the autonomic nervous system. Critically, autonomic reactivity predicts many mental states and, when synchronized, may reflect higher-order social processes like affiliation. Here, using data from 134 strangers interacting in pairs, we manipulated two features of social context to test their impact on synchrony in sympathetic and parasympathetic reactivity. Participants completed a knot-tying task within a collective reward (“cooperation”) or individual reward (“competition”) framework while conversing or not (“talking” condition). Autonomic reactivity varied by features of social context. Synchrony occurred across social contexts in both autonomic branches. We then examined how synchrony predicted affiliation. Sympathetic synchrony alone predicted affiliation yet social context and parasympathetic reactivity moderated associations between parasympathetic synchrony and affiliation. Thus, social and physiological context of parasympathetic synchrony predicted affiliation better than parasympathetic synchrony alone. We argue that social context and the degree of physiological reactivity underlying physiological synchrony, not the mere existence of physiological synchrony, are key to interpreting physiological synchrony as a social process.
Hurricane stalling along the North American coast and implications for rainfall
Authors: Hall Timothy M. , Kossin James P.
Published: June 2019

The average speed of tropical cyclone (TC) translation has slowed since the mid 20th century. Here we report that North Atlantic (NA) TCs have become increasingly likely to “stall” near the coast, spending many hours in confined regions. The stalling is driven not only by slower translation, but also by an increase in abrupt changes of direction. We compute residence-time distributions for TCs in confined coastal regions, and find that the tails of these distributions have increased significantly. We also show that TCs stalling over a region result in more rain on the region. Together, increased stalling and increased rain during stalls imply increased coastal rainfall from TCs, other factors equal. Although the data are sparse, we do in fact find a significant positive trend in coastal annual-mean rainfall 1948–2017 from TCs that stall, and we verify that this is due to increased stalling frequency. We make no attribution to anthropogenic climate forcing for the stalling or rainfall; the trends could be due to low frequency natural variability. Regardless of the cause, the significant increases in TC stalling frequency and high potential for associated increases in rainfall have very likely exacerbated TC hazards for coastal populations.
Best practices for analyzing large-scale health data from wearables and smartphone apps
Authors: Hicks Jennifer L. , Althoff Tim , Sosic Rok , Kuhar Peter , Bostjancic Bojan , King Abby C. , Leskovec Jure , Delp Scott L.
Published: June 2019

Smartphone apps and wearable devices for tracking physical activity and other health behaviors have become popular in recent years and provide a largely untapped source of data about health behaviors in the free-living environment. The data are large in scale, collected at low cost in the “wild”, and often recorded in an automatic fashion, providing a powerful complement to traditional surveillance studies and controlled trials. These data are helping to reveal, for example, new insights about environmental and social influences on physical activity. The observational nature of the datasets and collection via commercial devices and apps pose challenges, however, including the potential for measurement, population, and/or selection bias, as well as missing data. In this article, we review insights gleaned from these datasets and propose best practices for addressing the limitations of large-scale data from apps and wearables. Our goal is to enable researchers to effectively harness the data from smartphone apps and wearable devices to better understand what drives physical activity and other health behaviors.
Optimization and quantification of the systematic effects of a rolling circle filter for spectral pre-processing
Authors: Mirz Sebastian , Groessle Robin , Kraus Alexander
Published: June 2019

The presented method allows us to quantify and correct the systematic influence of a rolling circle filter for quantitative spectroscopic measurements.
Lowering the charge overpotential of Li2S via the inductive effect of phenyl diselenide in Li–S batteries
Authors: Fan Qianqian , Li Baohua , Si Yubing , Fu Yongzhu
Published: June 2019

We find that phenyl diselenide can lower the charge overpotential of Li2S via an inductive effect. The attraction between Se and Li weakens the Li–S bonds and facilitates the oxidation of Li2S in lithium batteries.
A reversed-phase/hydrophilic bifunctional interaction mixed-mode monolithic column with biphenyl and quaternary ammonium stationary phases for capillary electrochromatography
Authors: Mao Zhenkun , Hu Changjun , Li Zhentao , Chen Zilin
Published: June 2019

A novel RPLC/HILIC mixed-mode monolithic column with biphenyl and quaternary ammonium stationary phases is synthesized for capillary electrochromatography.
An electrochemical scaffold sensor for rapid syphilis diagnosis
Authors: Ogden Nathan E. , Kurnik Martin , Parolo Claudio , Plaxco Kevin W.
Published: June 2019

The faster a disease is diagnosed, the sooner treatment can be initiated, motivating a drive to replace standard laboratory techniques with point-of-care technology. Here we describe the development of an E-DNA sensor for the rapid measurement of anti-syphilis antibodies.
Identification of neural stem and progenitor cell subpopulations using DC insulator-based dielectrophoresis
Authors: Liu Yameng , Jiang Alan , Kim Estelle , Ro Clarissa , Adams Tayloria , Flanagan Lisa A. , Taylor Thomas J. , Hayes Mark A.
Published: June 2019

This study presents an unbiased high-resolution separation and characterization of NSPC subpopulations using direct current insulator-based dielectrophoresis.
Embedding cyclic nitrone in mesoporous silica particles for EPR spin trapping of superoxide and other radicals
Authors: Besson Eric , Gastaldi Stéphane , Bloch Emily , Zielonka Jacek , Zielonka Monika , Kalyanaraman Balaraman , Aslan Selma , Karoui Hakim , Rockenbauer Antal , Ouari Olivier , Hardy Micael
Published: June 2019

Mesoporous silica functionalised with a cyclic spin trap enabled the identification of a wide range of radicals in organic and aqueous media, including superoxide radical anion.