bluuebunny/crossref_metadata_2025 huggingface dataset:
From Elections to Democracy in Hard Times
Authors: Meyerrose Anna M. , Flores Thomas Edward , Nooruddin Irfan
Published: April 2019

The end of the Cold War, heralded as the ideological triumph of (Western) liberal democracy, was accompanied by an electoral boom and historically high levels of economic development. More recently, however, democratic progress has stalled, populism has been on the rise, and a number of democracies around the world are either backsliding or failing entirely. What explains this contemporary crisis of democracy despite conditions theorized to promote democratic success?

Research on democratization and democracy promotion tends to focus predominantly on elections. Although necessary for democracy, free and fair elections are more effective at promoting democratic progress when they are held in states with strong institutions, such as those that can guarantee the rule of law and constraints on executive power. However, increased globalization and international economic integration have stunted the development of these institutions by limiting states’ economic policy options, and, as a result, their fiscal policy space. When a state’s fiscal policy space—or, its ability to collect and spend revenue—is limited, governments are less able to provide public goods to citizens, politicians rely on populist rather than ideological appeals to win votes, and elections lose their democratizing potential.

Additional research from a political–economic framework that incorporates insights from studies on state building and institutions with recent approaches to democratization and democracy promotion, which focus predominantly on elections, is needed. Such a framework provides avenues for additional research on the institutional aspects of ongoing democratization and democratic backsliding.
Shedding Light on the Association between Night Work and Breast Cancer
Authors: Cherrie John W
Published: April 2019

Shift work that involves circadian disruption has been classified as probably carcinogenic to humans by the International Agency for Research on Cancer, although more recent epidemiological evidence is not consistent. Several mechanisms have been postulated to explain an association between night work and female breast cancer, but the most likely is suppression of the hormone melatonin by light exposure at night. Three articles recently published in this journal describe aspects of exposure to light during night work. These articles and other evidence suggest that nighttime light levels may not always be sufficient to affect melatonin production, which could in part explain the inconsistencies in the epidemiological data. There is need to improve the specificity and reliability of exposure assessments in future epidemiological studies of night shift workers.
Large-scale inference of competing endogenous RNA networks with sparse partial correlation
Authors: List Markus , Dehghani Amirabad Azim , Kostka Dennis , Schulz Marcel H
Published: April 2019

Motivation

MicroRNAs (miRNAs) are important non-coding post-transcriptional regulators that are involved in many biological processes and human diseases. Individual miRNAs may regulate hundreds of genes, giving rise to a complex gene regulatory network in which transcripts carrying miRNA binding sites act as competing endogenous RNAs (ceRNAs). Several methods for the analysis of ceRNA interactions exist, but these do often not adjust for statistical confounders or address the problem that more than one miRNA interacts with a target transcript.

Results

We present SPONGE, a method for the fast construction of ceRNA networks. SPONGE uses ’multiple sensitivity correlation’, a newly defined measure for which we can estimate a distribution under a null hypothesis. SPONGE can accurately quantify the contribution of multiple miRNAs to a ceRNA interaction with a probabilistic model that addresses previously neglected confounding factors and allows fast P-value calculation, thus outperforming existing approaches. We applied SPONGE to paired miRNA and gene expression data from The Cancer Genome Atlas for studying global effects of miRNA-mediated cross-talk. Our results highlight already established and novel protein-coding and non-coding ceRNAs which could serve as biomarkers in cancer.

Availability and implementation

SPONGE is available as an R/Bioconductor package (doi: 10.18129/B9.bioc.SPONGE).

Supplementary information

Supplementary data are available at Bioinformatics online.
Simplified pipelines for genetic engineering of mammalian embryos by CRISPR-Cas9 electroporation†
Authors: Miao Deqiang , Giassetti Mariana Ianello , Ciccarelli Michela , Lopez-Biladeau Blanca , Oatley Jon M
Published: April 2019

Gene editing technologies, such as CRISPR-Cas9, have important applications in mammalian embryos for generating novel animal models in biomedical research and lines of livestock with enhanced production traits. However, the lack of methods for efficient introduction of gene editing reagents into zygotes of various species and the need for surgical embryo transfer in mice have been technical barriers of widespread use. Here, we described methodologies that overcome these limitations for embryos of mice, cattle, and pigs. Using mutation of the Nanos2 gene as a readout, we refined electroporation parameters with preassembled sgRNA-Cas9 RNPs for zygotes of all three species without the need for zona pellucida dissolution that led to high-efficiency INDEL edits. In addition, we optimized culture conditions to support maturation from zygote to the multicellular stage for all three species that generates embryos ready for transfer to produce gene-edited animals. Moreover, for mice, we devised a nonsurgical embryo transfer method that yields offspring at an efficiency comparable to conventional surgical approaches. Collectively, outcomes of these studies provide simplified pipelines for CRISPR-Cas9-based gene editing that are applicable in a variety of mammalian species.
Ocean Floor Grab: International Law and the Making of an Extractive Imaginary
Authors: Ranganathan Surabhi
Published: April 2019

In this article, I argue for a critical recognition of the law of the sea, as it developed from the post-war period, as fostering a ‘grab’ of the ocean floor via national jurisdiction and international administration. I discuss why we should view what might be discussed otherwise as an ‘enclosure’ or ‘incorporation’ of the ocean floor within the state system as its grab. I then trace the grounds on which the ocean was brought within national and international regimes: the ocean floor’s geography and economic value. Both were asserted as givens – that is, as purely factual, but they were, in fact, reified through law. The article thus calls attention to the law’s constitutive effects. I examine the making of this law, showing that law-making by governments was influenced by acts of representation and narrative creation by many non-state actors. It was informed by both economic and non-economic influences, including political solidarity and suspicion, and parochial as well as cosmopolitan urges. Moreover, the law did not develop gradually or consistently. In exploring its development, I bring into focus the role played by one influential group of actors – international lawyers themselves.
On the Theory of Higher Rank Euler, Kolyvagin and Stark Systems
Authors: Burns David , Sano Takamichi
Published: April 2019

Mazur and Rubin have recently developed a theory of higher rank Kolyvagin and Stark systems over principal artinian rings and discrete valuation rings. We describe a natural extension of (a slightly modified version of) their theory to systems over more general coefficient rings. We also construct unconditionally, and for general $p$-adic representations, a canonical, and typically large, module of higher rank Euler systems and show that for $p$-adic representations satisfying standard hypotheses the image under a natural higher rank Kolyvagin-derivative-type homomorphism of each such system is a higher rank Kolyvagin system that originates from a Stark system.
Slightly Degenerate Categories and ℤ-Modular Data
Authors: Lacabanne Abel
Published: April 2019

Given a slightly degenerate braided pivotal fusion category $\mathscr{C}$, we explain how it naturally gives rise to a $\mathbb{Z}$-modular data. We do not restrict to spherical categories and work with pivotal categories. Finally, we give an interpretation in this framework of the Bonnafé–Rouquier categorification of the $\mathbb{Z}$-modular datum associated to nontrivial family of the cyclic complex reflection group.
Access of patients with breast and lung cancer to chemotherapy treatment in public and private hospitals in the city of Buenos Aires
Authors: Recondo Gonzalo , Cosacow César , Cutuli Hernán Javier , Cermignani Luciano , Straminsky Samanta , Naveira Martin , Pitzzu Martin , De Ronato Gabriela , Nacuzzi Gabriela , Taetti Gonzalo , Corsico Santiago , Berrueta Mabel , Colucci Giuliana , Gibbons Luz , Gutierrez Laura , García-Elorrio Ezequiel
Published: April 2019

Objectives

Describe the time elapsed from the diagnosis to treatment with chemotherapy for patients with breast and lung cancer at public and private hospitals in Buenos Aires.

Design

Retrospective cohort study.

Setting

Three public and three private academic hospitals in Buenos Aires.

Participants

Patients with breast (n = 168) or lung cancer (n = 100) diagnosis treated with chemotherapy.

Main outcomes measures

Clinical and sociodemographic data were collected in a stratified sample. We used the Kaplan–Meier estimator to analyse the time elapsed and the log rank test to compare both groups

Results

For breast cancer patients, median time elapsed between diagnosis and treatment with chemotherapy was 76 days (95% CI: 64–86) in public and 60 days (95% CI: 52–65) in private hospitals (P = 0.0001). For adjuvant and neoadjuvant treatments, median time was 130 (95% CI: 109–159) versus 64 (95% CI: 56–73) days (P < 0.0001) and 57 days (95% CI: 49–75) versus 26 (95% CI: 16–41) days, respectively (P = 0.0002). There were no significant differences in the time from first consultation to diagnosis. In patients with lung cancer, median time from diagnosis to treatment was 71 days (95% CI: 60–83) in public hospitals and 31 days (95% CI: 24–39) in private hospitals (P = 0.0002). In the metastatic setting, median time to treatment was 63 days (95% CI: 45–83) in public and 33 (95% CI: 26–44) days in private hospitals (P = 0.005).

Conclusions

There are significant disparity in the access to treatment with chemotherapy for patients in Buenos Aires, Argentina.
Cellular development in muscle differs between Angus steers from low and high muscle score selection lines1
Authors: Greenwood Paul L , O’Rourke Brendon A , Brunner Joe , Johns William H , Arthur Paul F , Cafe Linda M
Published: April 2019

This study assessed cellular characteristics of longissimus lumborum (LL) and semitendinosus (ST) muscles in steers genetically selected for low (Low) or high (High) muscling using live muscle scoring, and High steers with 1 copy of the loss-of-function 821 del11 MSTN allele (HighHet). We hypothesized High and HighHet have altered muscle cellular characteristics and mechanisms influencing muscling compared with Low steers. Angus steers 25 mo old comprising 14 High, 19 Low, and 11 HighHet were backgrounded to 20 mo of age, grain finished for 150 d, and then slaughtered. Body and carcass weights did not differ due to muscling line (P = 0.46). Weight of LL was 16% greater (P = 0.004) and total protein in LL was 18% greater (P = 0.012) in HighHet than Low steers. ST weight in HighHet was 10% and 13% greater than in High and Low steers (P = 0.007), respectively, and of total ST protein 12% and 17% greater in HighHet than High or Low (P = 0.002). Cross-sectional area (CSA) of LL was greater in HighHet than in High and greater in High than in Low (85.0 vs. 77.0 vs. 70.4 cm2, P < 0.001). Apparent number of myofibers and myofibers per unit CSA did not differ between the muscling lines in LL (P = 0.14) or ST (P = 0.47). Myofiber CSA was greater in the ST of Low than of High and HighHet for type 1 (36% and 31% respectively, P = 0.005) and 2A (22% and 25%, P < 0.001). HighHet steers had greater area of glycolytic (type 2X) relative to more oxidative myofiber types within LL (P = 0.02; 11% and 43% more than High and Low, respectively) and ST (P < 0.001; 27% and 75%). Concentration of RNA in LL was 13% and 10% greater (P = 0.005) in High than in Low and HighHet, respectively, and total amount of RNA in LL was 22% greater in High and 20% greater in HighHet than in Low (P < 0.001). The LL of High steers had less protein to RNA (P = 0.03; 57.4 vs. 65.6) and more RNA to DNA (P = 0.007; 9.03 vs. 7.83) than Low. HighHet steers had 11% more DNA in ST than High (P = 0.04) and 19% more RNA in ST than Low (P = 0.012). The shift towards glycolytic myofibers was consistent with loadings in a principal component that explained 39% of the variation in LL and 38% in ST. Overall, these findings show that selection for increased muscling using live cattle muscle scoring, and 1 copy of the 821 del11 MSTN allele, results in more glycolytic muscle. They also suggest that increased muscling of the High compared with Low steers may be associated with increased translational capacity in the LL.
Effect of whole foods and dietary patterns on markers of subclinical inflammation in weight-stable overweight and obese adults: a systematic review
Authors: Cowan Stephanie F , Leeming Emily R , Sinclair Andrew , Dordevic Aimee L , Truby Helen , Gibson Simone J
Published: April 2019

Context

Reduction of subclinical inflammation is a potential target for chronic disease management. Adiposity is a known modifier of meta-inflammation; however, the influence of dietary factors is less clear.

Objective

This review examines evidence from human trials evaluating effects of whole foods or dietary patterns on circulating inflammatory markers in weight-stable overweight and obese adults. It is the first review to investigate effects of diet on inflammation, independent of changes in adiposity.

Data Sources

The Ovid MEDLINE, EMBASE, CINAHL, and Cochrane databases were searched.

Data Extraction

Data extraction was conducted using the Cochrane Collaboration Handbook for Systematic Reviews of Interventions.

Data Analysis

Study quality was evaluated using the Cochrane Collaboration Risk of Bias Assessment tool. Thirty-three studies were included assessing effects of 17 foods and dietary patterns on 39 inflammatory markers.

Conclusions

Overall, foods and dietary patterns were not found to have significant effects on inflammatory markers in weight-stable individuals. Inconsistencies among studies were largely due to methodological limitations. Future research should invest in longer intervention periods and standardization of inflammatory marker panels paired with novel technologies, while ensuring anthropometric measures are monitored and adequately controls are used.

Systematic Review Registration

Prospero registration number CRD42017067765.
Bernard Lonergan
Authors: Byrne Patrick
Published: April 2019

As with many thinkers of his generation, the Canadian philosopher and theologian Bernard Joseph Francis Xavier Lonergan, SJ (b. 1904–d. 1984), sought to overcome the limitations of the traditions of thought that he inherited. Although a Catholic theologian by profession, he found it necessary to also think through major issues posed by modern philosophy, science, modern mathematics, the historical condition of humanity, economics, ethics, art, and education. He became best known for his theory of knowledge in the decades immediately following the publication of his masterwork, Insight: A Study of Human Understanding (1957). However, the discovery of his numerous unpublished writings following his death in 1984 required a major rethinking of his project. In light of those discoveries, his work on the theory of knowledge has come to be understood as one contribution to his broader effort to find an adequate way to think about and respond authentically to the human condition as historical. As he once put it, “All my work has been introducing history into Catholic theology.” He was dissatisfied with the static metaphysical context of the scholastic philosophy he was taught as a young man, as well as with the historicism that was adopted by many thinkers of the 19th and early 20th centuries. He refined his ideas in numerous unpublished essays, written both before and after the publication of Insight, that addressed the questions of historical process, knowledge, method, and responsibility. He has long been mistakenly categorized as a “transcendental Thomist,” and therefore rejected as a subjectivist and antirealist by many Thomist authors and teachers. It is certainly true that Lonergan was deeply indebted to the thought of Thomas Aquinas, but his studies found in Aquinas a theory of knowledge and a kind of realism that was, and still is, at odds with other prevailing Thomist interpretations. Prior to his two studies of Aquinas, he was already deeply influenced by his readings of Plato, John Henry Newman, Hegel, and Marx. These thinkers prepared him to find in Aquinas ideas that earlier scholars had overlooked—ideas that he would develop into his own unique treatments of knowledge, science, the natural world, history, truth, goodness, and God. He taught at the University of Toronto (Regis College), the Gregorian University (Rome), Harvard University, and Boston College.
Jean Genet
Authors: Hanrahan Mairéad
Published: April 2019

Jean Genet (b. 19 December 1910–d. 15 April 1986) was a 20th-century French poet, novelist, playwright, film director, essayist, and political activist. His work is renowned for its literary experimentation and poetic intensity and for its unequivocal opposition to the norms of bourgeois culture. Genet’s profile was singularly unconventional for a man of letters. His trajectory was far from traditional: abandoned by his mother when seven months old, he was placed in a foster family until his adolescence. He spent much of his teenage years in a reform school, Mettray, before joining the army only to desert soon afterward. Repeatedly convicted over the following decade for petty theft, he began to write in prison at the age of thirty. His use of highly poetic language in conjunction with an extremely explicit, unapologetic treatment of themes such as homosexuality and criminality won him recognition as a major literary figure in a remarkably short space of time. Within ten years, he had published a collection of poems as well as five dense prose texts and two plays, directed a film, and staged a ballet. Moreover, the prestigious publishing house Gallimard had commissioned his “Completed Works” in an unprecedented gesture for a living author, let alone one only forty years old. Genet then published very little over the next five years, before producing three plays in quick succession. Following the suicide of his lover in 1964, Genet claimed that he would write no more and he tore up his manuscripts; although the archives show that he continued to work on a number of projects, he would publish no further major work during his lifetime. He turned to political activism, culminating in 1970 when he accepted an invitation to tour the United States in support of the Black Panthers, and he spent six months with the Palestinian fedayeen in Jordan. By chance, he was one of the first people to enter the camps of Sabra and Shatila after the massacres in 1982; the experience appears to have been decisive in motivating him to return to writing. Although he had been diagnosed with throat cancer in 1979, he spent his final years working on a text about the Palestinian revolution. He died while correcting the proofs of this book, which was published posthumously one month later. He is buried in Larache, Morocco.
Jurij Lotman
Authors: Lorusso Anna Maria
Published: April 2019

Jurij (or Yuri) Lotman (b. 1922–d. 1993) was a Russian semiotician and cofounder of the Tartu-Moscow school of semiotics. A Russian philologist by education, his interests ranged from aesthetics to literary and cultural history; from narrative theory to intellectual history; from cinema to mythology. At the core of his theory is a holistic approach to culture as a system whose main feature is the modeling property. Culture is a structural mechanism that generates structurality through a primary modeling system (the verbal language) and secondary modeling systems (art, literature, religion, mythology, etc.). Clearly inspired in the 1970s by the emergence of structuralism in Moscow, over the years he gave an increasingly dynamic interpretation of “structure,” focusing on the evolution of systems and continuous hybridizations of languages. The idea of dialogue as a condition for cultural evolution is a personal echo of Bakhtin’s theory, which assumes an absolute centrality in Lotman. Cultural evolution comes from the relationship with the Other and the exchange with spaces different from our own. In this frame, the idea of border is also pivotal: cultural identities need to define their own borders, but it is precisely on the borders—lines of separation—that we find the maximum exchange. These ideas form the basis of the theory of semiosphere, a successful neologism that, echoing the biosphere of Vernadskij, points out the holistic, functional, and self-organized quality of cultural systems. In his last works (published posthumously in 2009 and 2013), Lotman’s interest in history and temporal layers of cultures is increasingly in the foreground. He focuses on the predictability or otherwise of historical situations, putting the category of explosion at the center of his reflection, as a moment of unexpected acceleration of the historical-cultural dynamism and the creativity of systems. During the 1970s, Lotman’s works and those of other Soviet semioticians were widely read and proved influential, especially in the field of Slavic studies. In the 1980s, they become influential in American and West European academia. Among the scholars who used Lotman’s concepts are the philosopher Paul Ricoeur, the New Historicist Stephen Greenblatt, the semiotician Umberto Eco, the reception theorist Wolfgang Iser, and the feminist critic Julia Kristeva. From 2000s onward, Lotman’s legacy has been pivotal in the field of semiotics, and relevant also to the field of cultural and media studies.
The American Negro Theatre
Authors: Shandell Jonathan
Published: April 2019

From the group’s first public performance in June 1940 until its collapse in late 1949 or early 1950, the American Negro Theatre (ANT) stood as Harlem’s preeminent theatrical organization. From modest beginnings (including an initial treasury of less than twenty cents), this company grew in visibility and prestige, achieving prominence both in Harlem and on Broadway, and influencing the evolution of American culture with respect to inclusion of black artists and representations of race. The ensemble achieved new heights for African American artistic autonomy and self-expression within the theater. At the same time, the ANT undertook groundbreaking interracial collaborations and advanced the cause of integration in the theater, through its frequent partnerships with white artists. The ANT’s ongoing fame derives in large part from the accomplishments and visibility achieved by many of its alumni as professional artists, following the company’s demise. Ruby Dee, Sidney Poitier, Harry Belafonte, Earle Hyman, Alice Childress, Clarice Taylor, Frederick O’Neal, William Greaves, and many others worked with ANT early in their careers—gaining experience and training that helped propel them into greater public visibility later in life. Another source of renown for the ANT was the creation of the wildly popular Anna Lucasta—which began in Harlem before transferring to a historic two-year run on Broadway, an engagement in London’s West End, and two Hollywood film adaptations. Anna Lucasta still stands as the longest-running play in Broadway history with an entirely African American cast. Despite its collapse amid financial hardships after ten years of activity, the ANT’s influence—both on African American cultural expression as well as on commercial entertainment in the United States—has been transformative and far-reaching.
Ethnography in Antiquity
Authors: Redfield James Adam
Published: April 2019

Today “ethnography” refers to three things simultaneously: it is a term for a body of scientific knowledge; a method for acquiring it; and a mode of representing it. Historically, however, we can disentangle those meanings. The first is only modern; the second can bear traces of Antiquity; the third is organically ancient. Scholarly use of the label is modern (in German, 1767; in Russian, 1802; in French, 1823; in English, 1834), as are the institutions and discourses where it came to refer to a body of scientific knowledge. In this sense, there is no ethnography before the Enlightenment sciences (or proto- and pseudo- forms) which coined it. Ethnography as a method is no less defined by the various fields where it is used. Yet ethnography is also used in humanistic fields (history; geography; law; theology; the arts) with deeper roots in Antiquity. In those fields, ethnography assimilates ancient sources and, occasionally, ancient ways of thinking. The humanities also hybridize with modern sciences to form new fields (e.g., Mediterranean Studies). This is another vector along which ethnographic methods transact with Antiquity. Finally, even modern sciences are eclectic in their methods, as when anthropologists adapt ancient theological categories to organize their fieldwork. In sum, prominent definitions of the ethnographic method (e.g., “participant observation”) are modern. Yet in practice, ethnography has been, and still is, not infrequently guided by ancient problems and perspectives. Finally, as a mode of representation, we do find ethnography in ancient authors, defined here by two basic shared interests. First: how and why human groups differ, in their inner and outer qualities, often using the author’s own group as a basis for comparison. Second, in order to analyze such differences, these ancient writers develop what we call ethnology: theories of peoplehood, including categories and hierarchies for classifying peoples. Ancient ethnography and ethnology are thus sites for the formation of concepts that, in complex ways, overlap with modern concepts like race; ethnicity; gender; nation; civilization; religion; and culture. Ancient ethnography often takes the form of apparent digressions in other Genres such as history, where writers survey a people’s customs, physical characteristics, habitat, virtues and vices, grafting their sources and observations onto literary models. These representations of self and other in Antiquity left a rich legacy, extending into the medieval and early modern eras. Approaches have been developed for comparing them to later ethnography—not only in terms of direct influence, but also in light of analogous literary and conceptual patterns.
BONNER CYLINDER SET FOR NEUTRON SPECTROSCOPY AT HIGH ENERGY ACCELERATORS
Authors: Sokolov Alexey , Kozlova Ekaterina , Radon Torsten
Published: April 2019

At particle accelerators, the knowledge of neutron spectra is important for radiation protection to improve the accuracy of dose measurements, for activation and radiation damage studies. Classical Bonner sphere spectrometer is a common reliable tool for this kind of measurements. Here we present a new set of cylinders with TLD cards as a sensitive element to be used for neutron spectroscopy in a wide energy range for continuous and ultra-short pulse radiation. A simple layout, relatively small dimensions and weight, as well as implementation of common materials providing low construction costs make the set useful for spectroscopic purposes. The unfolding results for various simulated radiation scenarios are also presented.
Interaction between DNA damage response, translation and apoptosome determines cancer susceptibility to TOP2 poisons
Authors: Awah Chidiebere U , Chen Li , Bansal Mukesh , Mahajan Aayushi , Winter Jan , Lad Meeki , Warnke Louisa , Gonzalez-Buendia Edgar , Park Cheol , Daniel Zhang , Feldstein Eric , Yu Dou , Zannikou Markella , Balyasnikova Irina V. , Martuscello Regina , Konerman Silvana , Győrffy Balázs , Burdett Kirsten B , Scholtens Denise M , Stupp Roger , Ahmed Atique , Hsu Patrick , Sonabend Adam
Published: April 2019

Topoisomerase II poisons are one of the most common class of chemotherapeutics used in cancer. We show that glioblastoma (GBM), the most malignant of all primary brain tumors in adults is responsive to TOP2 poisons. To identify genes that confer susceptibility to this drug in gliomas, we performed a genome-scale CRISPR knockout screen with etoposide. Genes involved in protein synthesis and DNA damage were implicated in etoposide susceptibility. To define potential biomarkers for TOP2 poisons, CRISPR hits were overlapped with genes whose expression correlates with susceptibility to this drug across glioma cell lines, revealing ribosomal protein subunit RPS11, 16, 18 as putative biomarkers for response to TOP2 poisons. Loss of RPS11 impaired the induction of pro-apoptotic gene APAF1 following etoposide treatment, and led to resistance to this drug and doxorubicin. The expression of these ribosomal subunits was also associated with susceptibility to TOP2 poisons across cell lines from multiple cancers.

Graphical Abstract
A Bayesian Monte Carlo approach for predicting the spread of infectious diseases
Authors: Stojanović Olivera , Leugering Johannes , Pipa Gordon , Ghozzi Stéphane , Ullrich Alexander
Published: April 2019

In this paper, a simple yet interpretable, probabilistic model is proposed for the prediction of reported case counts of infectious diseases. A spatio-temporal kernel is derived from training data to capture the typical interaction effects of reported infections across time and space, which provides insight into the dynamics of the spread of infectious diseases. Testing the model on a one-week-ahead prediction task for campylobacteriosis and rotavirus infections across Germany, as well as Lyme borreliosis across the federal state of Bavaria, shows that the proposed model performs on-par with the state-of-the-arthhh4model. However, it provides a full posterior distribution over parameters in addition to model predictions, which aides in the assessment of the model. The employed Bayesian Monte Carlo regression framework is easily extensible and allows for incorporating prior domain knowledge, which makes it suitable for use on limited, yet complex datasets as often encountered in epidemiology.

Author summary

Why was this study done?

Statistical modeling is invaluable to public-health policy as it helps understand and anticipate the dynamics of the spread of infectious diseases. The available training data is often limited and reported with a low spatial and temporal resolution. This poses a challenge and makes it particularly important to incorporate domain knowledge and prior assumptions to guide the modeling process.

In order to evaluate the trustworthiness and reliability of a model’s predictions, it is crucial to be able to interpret the model and quantify the model uncertainty.

To address this, we develop an interpretable model that uses Bayesian inference (rather than commonly used maximum likelihood estimation) and provides a probability distribution over inferred parameters.

What did the researchers do and find?

We develop and test a single probabilistic model that learns to predict the number of weekly case counts for three different diseases (campylobacteriosis, rotaviral enteritis and Lyme borreliosis) at the county level one week ahead of time.

We employ a Bayesian Monte Carlo regression approach that provides an estimate of the full probability distribution over inferred parameters as well as model predictions.

The model learns an interpretable spatio-temporal kernel that captures typical interactions between infection cases of the tested diseases.

The predictive performance of our model compares favorably with a contemporary reference model for all diseases tested.

What do these findings mean?

Interpretable predictive models can be applied to surveillance data to gain insights into the dynamics of infectious diseases.

Probabilistic modeling approaches provide a suitable framework for many challenges of working with epidemiological data.
CTCF-dependent chromatin boundaries formed by asymmetric nucleosome arrays with decreased linker length
Authors: Clarkson Christopher T. , Deeks Emma A. , Samarista Ralph , Mamayusupova Hulkar , Zhurkin Victor B. , Teif Vladimir B.
Published: April 2019

The CCCTC-binding factor (CTCF) organises the genome in 3D through DNA loops and in 1D by setting boundaries isolating different chromatin states, but these processes are not well understood. Here we focus on the relationship between CTCF binding and the decrease of the Nucleosome Repeat Length (NRL) for ∼20 adjacent nucleosomes, affecting up to 10% of the mouse genome. We found that the chromatin boundary near CTCF is created by the nucleosome-depleted region (NDR) asymmetrically located >40 nucleotides 5’-upstream from the centre of CTCF motif. The strength of CTCF binding to DNA is correlated with the decrease of NRL near CTCF and anti-correlated with the level of asymmetry of the nucleosome array. Individual chromatin remodellers have different contributions, with Snf2h having the strongest effect on the NRL decrease near CTCF and Chd4 playing a major role in the symmetry breaking. Upon differentiation of embryonic stem cells to neural progenitor cells and embryonic fibroblasts, a subset of common CTCF sites preserved in all three cell types maintains a relatively small local NRL despite genome-wide NRL increase. The sites which lost CTCF upon differentiation are characterised by nucleosome rearrangement 3’-downstream, but the boundary defined by the NDR 5’-upstream of CTCF motif remains.
Genomic hypervariability of phage Andromeda is unique among known dsDNA viruses
Authors: Magill Damian J. , Kulakov Leonid A. , Skvortsov Timofey A.
Published: April 2019

A new lytic bacteriophage Andromeda, specific to the economically important plant pathogenPseudomonas syringae, was isolated and characterised. It belongs to thePodoviridaefamily,Autographivirinaesubfamily and possesses a linear dsDNA genome of 40,008 bp with four localised nicks. Crucially, Andromeda’s genome has no less than 80 hypervariable sites (SNPs), which show genome wide distribution resulting in heterogenous populations of this phage reminiscent of those of RNA virus quasispecies. Andromeda has no nucleotide sequence homology to phage phiNFS, a member ofphiKMVviruses, in which a similar phenomenon was discovered. We show that Andromeda and Andromeda-related phages form a group within theAutographivirinae, designated here as the “ExophiKMVviruses”. The “ExophiKMVviruses” were revealed to share conservation of gene order with corephiKMVvirusesdespite their sequence-based relationship to SP6-related phages. Our findings suggest that genomic hypervariability might be a feature that occurs among variousAutographivirinaegroups.
GABA-A signaling maintains melanocyte stem cell quiescence in larval zebrafish
Authors: Allen James R. , Skeath James B. , Johnson Stephen L.
Published: April 2019

Adult stem cells (ASCs) contribute to long-term homeostasis and regeneration of many adult tissues. Some ASCs proliferate continuously, others remain quiescent awaiting activation. To identify pathways that regulate ASC quiescence and tissue homeostasis, we study melanocyte stem cells (MSCs) that drive vertebrate pigmentation. In larval zebrafish, MSCs are quiescent, but can be recruited to regenerate the larval pigment pattern following melanocyte ablation. Through pharmacological experiments, we found that inhibition of GABA-A receptor function, specifically the GABA-A rho subtype, induces excessive melanocyte production in larval zebrafish. Conversely, pharmacological activation of GABA-A inhibited melanocyte regeneration. We used CRISPR to generate two mutant alleles ofgabrr1, a subtype of GABA-A. Both alleles exhibited robust melanocyte overproduction, while conditional overexpression ofgabrr1inhibited larval melanocyte regeneration. Our data suggest thatgabrr1signaling is necessary and sufficient to maintain MSC quiescence and prevent excessive pigmentation of the larval zebrafish.
Elimination of reference mapping bias reveals robust immune related allele-specific expression in crossbred sheep
Authors: Salavati Mazdak , Bush Stephen J. , Palma-Vera Sergio , McCulloch Mary E. B. , Hume David A. , Clark Emily L.
Published: April 2019

Pervasive allelic variation at both gene and single nucleotide level (SNV) between individuals is commonly associated with complex traits in humans and animals. Allele-specific expression (ASE) analysis, using RNA-Seq, can provide a detailed annotation of allelic imbalance and infer the existence of cis-acting transcriptional regulation. However, variant detection in RNA-Seq data is compromised by biased mapping of reads to the reference DNA sequence. In this manuscript we describe an unbiased standardised computational pipeline for allele-specific expression analysis using RNA-Seq data, which we have adapted and developed using tools available under open licence. The analysis pipeline we present is designed to minimise reference bias while providing accurate profiling of allele-specific expression across tissues and cell types. Using this methodology, we were able to profile pervasive allelic imbalance across tissues and cell types, at both the gene and SNV level, in Texel x Scottish Blackface sheep, using the sheep gene expression atlas dataset. ASE profiles were pervasive in each sheep and across all tissue types investigated. However, ASE profiles shared across tissues were limited and instead they tended to be highly tissue-specific. These tissue-specific ASE profiles may underlie the expression of economically important traits and could be utilized as weighted SNVs, for example, to improve the accuracy of genomic selection in breeding programmes for sheep. An additional benefit of the pipeline is that it does not require parental genotypes and can therefore be applied to other RNA-Seq datasets for livestock, including those available on the Functional Annotation of Animal Genomes (FAANG) data portal. This study is the first global characterisation of moderate to extreme ASE in tissues and cell types from sheep. We have applied a robust methodology for ASE profiling, to provide both a novel analysis of the multi-dimensional sheep gene expression atlas dataset, and a foundation for identifying the regulatory and expressed elements of the genome that are driving complex traits in livestock.
Calibrating seed-based alignment heuristics with Sesame
Authors: Filion Guillaume J. , Cortini Ruggero , Zorita Eduard
Published: April 2019

The increasing throughput of DNA sequencing technologies creates a need for faster algorithms. The fate of most reads is to be mapped to a reference sequence, typically a genome. Modern mappers rely on heuristics to gain speed at a reasonable cost for accuracy. In the seeding heuristic, short matches between the reads and the genome are used to narrow the search to a set of candidate locations. Several seeding variants used in modern mappers show good empirical performance but they are difficult to calibrate or to optimize for lack of theoretical results. Here we develop a theory to estimate the probability that the correct location of a read is filtered out during seeding, resulting in mapping errors. We describe the properties of simple exact seeds, skip-seeds and MEM seeds (Maximal Exact Match seeds). The main innovation of this work is to use concepts from analytic combinatorics to represent reads as abstract sequences, and to specify their generative function to estimate the probabilities of interest. We provide several algorithms, which combined together give a workable solution for the problem of calibrating seeding heuristics for short reads. We also provide a C implementation of these algorithms in a library called Sesame. These results can improve current mapping algorithms and lay the foundation of a general strategy to tackle sequence alignment problems. The Sesame library is open source and available for download at https://github.com/gui11aume/sesame.
Gene Therapy for Follistatin Mitigates Systemic Metabolic Inflammation and Post-Traumatic Osteoarthritis in High-Fat Diet-Induced Obese Mice
Authors: Tang Ruhang , Harasymowicz Natalia S. , Wu Chia-Lung , Collins Kelsey H. , Choi Yun-Rak , Oswald Sara J. , Guilak Farshid
Published: April 2019

Obesity-associated inflammation and loss of muscle function play critical roles in the development of osteoarthritis (OA); thus, therapies that target muscle tissue may provide novel approaches to restoring metabolic and biomechanical dysfunction associated with obesity. Recent studies indicate that follistatin (FST), a protein which binds myostatin and activin, may have the potential to enhance muscle formation while neutralizing inflammation induced by these proteins. Here, we hypothesized that adeno-associated virus (AAV9) delivery of FST will enhance muscle formation and mitigate metabolic inflammation and knee OA caused by a high fat diet in mice. Obese mice receiving AAV-mediated FST delivery exhibited decreased inflammatory adipokines and cytokines systemically in the serum as well as locally in the joint synovial fluid. Regardless of diet, mice receiving FST gene therapy were protected from post-traumatic OA and bone remodeling induced by joint injury. While obesity disrupted the mitochondrial oxidative phosphorylation (OXPHOS) system in adipocytes, gene therapy for FST restored the key proteins involved in mitochondrial biogenesis, such as PPARγ coactivator 1α and AKT protein kinase 1, leading to the browning of white adipose tissue. Taken together, these findings suggest that FST gene therapy may provide a multifactorial therapeutic approach for injury-induced OA and metabolic inflammation in obesity.
Recessive genetic effects on type 2 diabetes-related metabolites in a consanguineous population
Authors: Demirkan Ayşe , Liu Jun , Amin Najaf , van Klinken Jan B , van Dijk Ko Willems , van Duijn Cornelia M.
Published: April 2019

Autozygosity, meaning inheritance of an ancestral allele in the homozygous state is known to lead bi-allelic mutations that manifest their effects through the autosomal recessive inheritance pattern. Autosomal recessive mutations are known to be the underlying cause of several Mendelian metabolic diseases, especially among the offspring of related individuals. In line with this, inbreeding coefficient of an individual as a measure of cryptic autozygosity among the general population is known to lead adverse metabolic outcomes including Type 2 diabetes (T2DM); a multifactorial metabolic disease for which the recessive genetic causes remain unknown. In order to unravel such effects for multiple metabolic facades of the disease, we investigated the relationship between the excess of homozygosity and the metabolic signature of T2DM. We included a set of 53 metabolic phenotypes, including 47 metabolites, T2DM and five T2DM risk factors, measured in a Dutch genetic isolate of 2,580 people. For 20 of these markers, we identified 29 regions of homozygous (ROHs) associated with the nominal significance of P-value < 1.0 × 10−3. By performing association according to the recessive genetic model within these selected regions, we identified and replicated two intronic variants: rs6759814 located inKCNH7associated with valine and rs1573707 located inPTPRTassociated with IDL-free cholesterol and IDL-phospholipids. Additionally, we identified a rare intronic SNV inTBR1for which the homozygous individuals were enriched for obesity. Interestingly, all three genes are mainly neuronally expressed and pointed out the involvement of glutamergic synaptic transmission pathways in the regulation of metabolic pathways. Taken together our study underline the additional benefits of model supervised analysis, but also seconds the involvement of the central nervous system in T2DM and obesity pathogenesis.
Rapid, Low-Cost Detection of Water Contaminants Using RegulatedIn VitroTranscription
Authors: Alam Khalid K. , Jung Jaeyoung K. , Verosloff Matthew S. , Clauer Phillip R. , Lee Jeong Wook , Capdevila Daiana A. , Pastén Pablo A. , Giedroc David P. , Collins James J. , Lucks Julius B.
Published: April 2019

Synthetic biology has enabled the development of powerful nucleic acid diagnostic technologies for detecting pathogens and human health biomarkers. Here we expand the reach of synthetic biology-enabled diagnostics by developing a cell-free biosensing platform that usesRNAoutputsensorsactivated by ligandinduction (ROSALIND) to detect harmful contaminants in aqueous samples. ROSALIND consists of three programmable components: highly-processive RNA polymerases, allosteric transcription factors, and synthetic DNA transcription templates. Together, these components allosterically regulate thein vitrotranscription of a fluorescence-activating RNA aptamer: in the absence of a target compound, transcription is blocked, while in its presence a fluorescent signal is produced. We demonstrate that ROSALIND can be configured to detect a range of water contaminants, including antibiotics, toxic small molecules, and metals. Our cell-free biosensing platform, which can be freeze-dried for field deployment, creates a new capability for point-of-use monitoring of molecular species to address growing global crises in water quality and human health.
Macromolecular crowding links ribosomal protein gene dosage to growth rate inVibrio cholerae
Authors: Soler-Bistué Alfonso , Aguilar-Pierlé Sebastián , Garcia-Garcerá Marc , Val Marie-Eve , Sismeiro Odile , Varet Hugo , Sieira Rodrigo , Krin Evelyne , Skovgaard Ole , Comerci Diego J. , Rocha Eduardo P. C. , Mazel Didier
Published: April 2019

Ribosomal protein (RP) genes locate near the replication origin (oriC) in fast-growing bacteria, which is thought to have been selected as a translation optimization strategy. Relocation ofS10-spc-αlocus (S10), which codes for most of the RP, to ectopic genomic positions shows that its relative distance to theoriCcorrelates to a reduction on its dosage, its expression, and bacterial growth rate. Deep-sequencing revealed that S10 relocation altered chromosomal replication dynamics and genome-wide transcription. Such changes increased as a function oforiC-S10 distance. Strikingly, in this work we observed that protein production capacity was independent of S10 position. Since RP constitute a large proportion of cell mass, lower S10 dosage could lead to changes in macromolecular crowding, impacting cell physiology. Accordingly, cytoplasm fluidity was higher in mutants where S10 is most distant fromoriC. In hyperosmotic conditions, when crowding differences are minimized, the growth rate and replication dynamics were highly alleviated in these strains. Therefore, on top of its essential function in translation, RP genomic location contributes to sustain optimal macromolecular crowding. This is a novel mechanism coordinating DNA replication with bacterial growth.