bluuebunny/crossref_metadata_2025 huggingface dataset:
Brigadoon and Its Transition to MGM Dance Musical
Authors: Smith Susan
Published: July 2019

This chapter offers an analysis of Gene Kelly and Cyd Charisse’s contribution to the MGM adaptation of Brigadoon. On the stage, this musical was designed for singers, but the film version cast Kelly and Charisse, the latter replacing soprano Kathryn Grayson, who was the original choice for the character of Fiona. This necessitated enormous changes to the Broadway material, including the deletion of some of the most vocally demanding songs (‘There But for You Go I’ and ‘From This Day On’) and the reworking of ‘The Heather on the Hill’ and ‘Almost Like Being in Love’ into solos for Tommy (Kelly) rather than duets for Tommy and Fiona. Kelly’s presence also meant that he served, naturally, as the film’s choreographer, replacing Agnes de Mille, whose choreography had been one of the cornerstones of the Broadway production. Because the leads were now dancers, with additional opportunities for them to dance added to the piece, the role of Harry Beaton, which had revolved around the famous Sword Dance on the stage, was reduced and his number cut. Yet the chapter also identifies benefits from the casting changes and argues that it is one of MGM’s most underrated musicals, gaining tension and complexity from some of its perceived flaws.
Children and Juvenile Justice Law
Authors: Hollingsworth Kathryn
Published: July 2019

Despite comprehensive international standards, children’s rights continue to be breached in juvenile justice systems around the world. This chapter suggests that conceptualizing children, autonomy, and—by extension—their rights as relational may improve rights protection for children who are in conflict with the law. It offers four justifications for a relational approach to juvenile justice—the descriptive, methodological, normative, and conceptual. The chapter then applies a relational framework to the specific context of juvenile justice rights in England and Wales and identifies three jurisprudential trends which, it suggests, indicate a partial shift by (some) courts towards a relational approach. However, there is still a considerable way to go before relationality goes beyond the superficial to become fully embedded as the basis for children’s rights in juvenile justice law. The chapter concludes by suggesting therefore, that as well as examining how the concept of autonomy is conceptualized in juvenile justice rights, we must also unpack and explore how the courts understand the concept of autonomy per se, if we are to achieve greater compliance with international rights standards.
The Promises and Pitfalls of Constitutionalizing Children’s Rights
Authors: O’Mahony Conor
Published: July 2019

In 2012, the Irish Constitution was amended by the insertion of a new provision focused on children’s rights. This amendment marked the culmination of a twenty-year campaign driven in large part by the opinion that the Constitution overemphasized the rights of parents and the family unit to the detriment of the rights of children. Campaigners hailed the outcome of the referendum as a historic day, but academic opinion has been more cautious about the true impact and potential of the final version. This article examines the lessons of the Irish experience by first exploring the reasons why children’s rights might be constitutionalized. It then examines the background to the Irish amendment, before drawing some conclusions on its impact and on what can be learned from the Irish experience on the value and limitations of constitutional change as a vehicle for advancing children’s rights.
Lobbying Networks
Authors: Victor Jennifer Nicoll
Published: July 2019

While lobbyists are colloquially thought of as parasites on US democracy, this article offers the perspective that lobbyists are part of vital connective tissue that facilitates interaction between principal players and institutions of policymaking. After a brief review of the history of lobbying in the United States, the article outlines four paradigmatic lenses through which lobbying has been understood—pluralist, realist, behavioral, and relational. It then makes the case that the relational lens is the most productive means of studying and understanding the role of lobbying in the United States. The article concludes with noting the considerable challenges to this field of study.
Do Election Campaigns Matter?
Authors: Branham J. Alexander , Wlezien Christopher
Published: July 2019

Do election campaigns matter? This chapter examines whether and how they do. It considers when they occur, what they do, and what effects they can have. Although candidates and parties would like to directly persuade individuals, it is difficult to detect those kinds of effects at the aggregate level since the effects are small and polling is imprecise. The chapter then introduces the “timeline” of elections and how we can observe preferences change and harden as the election approaches. This method allows us to test various hypotheses, such as whether political institutions matter for the evolution of electoral preferences over the timeline. The chapter concludes with a discussion of mobilization, which is a cost-effective way that campaigns can persuade people to vote who would not have otherwise.
White Woman’s Burden and the Bible during the British Occupation of Singapore
Authors: Lim Chin Ming Stephen
Published: July 2019

This essay explores the use of the Bible in one periphery of the British Occupation in the nineteenth century: Singapore at the intersection of gender and Empire. The key line of inquiry is to explore what Antoinette Burton outlines as the “white woman’s burden,” manifested in the Singaporean context through the use of the Bible by white women and their protégés. Therefore, this essay begins with how the work of white women is entangled with the interests of the Empire and then analyzes the periodical The Christian in Singapore: A Religious Magazine, which was published by the Ladies Bible and Tract Society in Singapore. This is followed by a closer look at education and women in the Church Missionary Society periodicals. The discussion focuses particularly on the biography of Sophia Cooke, a prominent missionary in Singapore, as well as a regional publication, India’s Women and China’s Daughters.
The Simplest Model of Global Governance Ever Seen?
Authors: Sgard Jérôme
Published: July 2019

From the 1880s till 1930, the global grain trade was regulated primarily by the London Corn Trade Association, a private body entirely controlled by core market insiders. It had three defining contributions: it produced grain standards, which transformed cereals into commodities; it arbitrated disputes between traders; and it drafted some sixty standard contracts that were minutely adjusted to both the trading rules in exporting countries and to standard contracts for shipping, insurance, and trade credit. These transnational contractual vehicles drastically simplified the successive operations of international trade along the whole value chain. Critically, while the contracts were governed by English law and protected by the London courts, they entirely avoided any relations with other national legal orders or jurisdictions. Conflicts of laws, a perennial source of transaction costs in a global economy, were by and large eschewed by means of a private market order that was both local and global.
The Political and Professional Economies of US Global Corporate Criminal Enforcement
Authors: Buell Samuel W.
Published: July 2019

This chapter seeks to explain to a mostly international and non-legal audience what drives and shapes the practices of prosecutors in their enforcement of US criminal law against corporations and their agents for conduct outside the United States. This explanation must begin with US law, which has jurisdictional and other features that afford American prosecutors unparalleled leeway and reach. Much more of the explanation for enforcement behaviors, however, lies in the political and professional economies that determine the incentives and choices of the US Department of Justice and its individual prosecutors. This explanation requires an understanding of the domestic political economy of criminal enforcement within the United States and the distinctive structure and culture of the American bar. Beyond this descriptive work, the chapter considers what might lie ahead as present US prosecutorial practices, which have been driven mostly by domestic influences, increasingly run into, or are pursued by, the prosecutorial practices of other nations, as well as attitudes toward prosecution in those nations.
Leading in Higher Education
Authors: van Rooijen Maurits
Published: July 2019

This chapter considers the higher education leader’s perspective in conjunction with the following themes: (1) the leader as a change agent, responding to mega trends (globalization, digitalization and the demands of knowledge-based economies); (2) the challenge of choosing the right gear of change (evolution, rapid evolution, revolution) whilst executing transformations; (3) the recognition at all levels (macro, meta, micro) of the value of diversity, and understanding that institutions are typically a blend of three ultra-types (knowledge for the sake of knowledge; utilitarian, accountable institution; sustainable enterprises) and the importance of matching leadership; (4) understanding the alignment of ‘ABC’ (academic aspiration, business, communities) whilst enlarging C through emotional engagement; and (5) the imperative to secure funding to achieve strategic objectives and institutional sustainability (fundraising, public–private partnerships, cooperative constructions). Current funding realities suggest big is truly beautiful but this risks diminishing diversity.
Criticality, Academic Autonomy, and Societal Progress
Authors: Redding Gordon
Published: July 2019

To avoid ethnocentric analysis, HE’s role in societal progress may be placed in a context that is abstract enough to be taken as universally applicable, even though the interpretation of its principles is likely to differ between societies and cultures. The literature on development is reviewed to extract core principles that may be conjectured as universal on historical evidence to date. These are specified as capabilities achieved by a society that allow it to adapt to surrounding change, and still remain cohesive. HE can play a significant part in building these capabilities, in its work to transform both individuals and societies. Key catalysts would be scholarship, reasoned analysis, and moral frameworks to support social fusion and incentives to adapt.
Governments Need To, and Do, Trust Universities
Authors: Calford Mike B.
Published: July 2019

Through direct support funding, granting agencies, student scholarships, tax concessions, and other sources governments provide the vast bulk of funding to operate universities. However, governments cede control of how those funds are used to the universities, and these cede control of curricula, assessment, and standards to their academics. Why is this the case for almost all successful university systems? The usual explanation, that the best outcomes of academic pursuit occur with distributed decision making, is simply another description of what has been common in successful systems of higher education under multiple jurisdictions. An answer may come from the consideration that, typically, governments and universities operate on very different timescales. The academic cycles for teaching and research (ten to twenty-five years) far exceed the span of most government administrations (three to five years).
Policy Implications for Equity, Gender, and Widening Participation in Higher Education
Authors: Burke Penny Jane , David Miriam E. , Moreau Marie-Pierre
Published: July 2019

This chapter examines the intersecting inequalities and differences in HE that persist despite decades of HE policy focused on equity and widening participation. Attention is given to the ways that patriarchy, neo-liberalism, corporatization, and managerialism work together to generate new forms of inequality and power relations, which include inequalities in access and participation, women in leadership positions, sexual assault or harassment on campus, care-less university cultures, and complex temporal inequalities. The chapter examines the emergence of widening participation and equity policies in many countries of both the global North and the global South whilst the forces of globalization, neo-liberalism, and marketization have repositioned students as consumers of the market of higher education. It shows how these forces have produced an individualizing focus on student and staff experience, concealing the contextual, temporal, and structural inequalities that profoundly undermine policy concerns to widen access and participation. Individualism and marketization impact student and staff experiences in relation to the different social location and the gendering of education, work, and family, which privileges the productive (with a focus on paid labour and employability) over the reproductive (with a focus on unpaid labour and caring) dimensions of social life. The chapter shows the power of feminist analyses of questions of equity and widening participation to bring to light the insidious ways that inequalities are reproduced through the neo-liberal, patriarchal university.
Socializing Human Capital for Twenty-First Century Educational Goals
Authors: Bond Michael H. , Jing Yiming
Published: July 2019

Crucial to global HE are the differences in the socialization processes that prepare students prior to their entry to universities. This preparation is analysed to reveal variations that are likely to affect the building in a society of the human capital capabilities: cognitive, empathetic, and interpersonal. The nature and availability of these resources is seen as key to a society’s ability to generate innovativeness and cooperativeness. Data are analysed from representative populations in seventy-nine nations positioned in a two-dimensional matrix of Practicality vs. Civility and Other-directedness vs. Self-directedness. This mapping permits comparison between societies on the initial mental structures of meaning and relevance brought by students into a nation’s classrooms. Implications are drawn for current forecasts of skills appropriate to living in twenty-first century conditions.
The Implications of a Diversifying Workforce for Institutional Governance and Management in Higher Education
Authors: Whitchurch Celia
Published: July 2019

Contemporary influences on institutional policy and practice are analysed based on studies in 23 HE institutions in the United Kingdom, involving 183 interviews. The implications of a diversifying workforce are considered in the context of institutional responses to more market-oriented systems, and the delicate balance with traditional academic governance. In particular, consideration is given to the critical role of middle managers such as heads of department and research leaders in adjusting and implementing institutional policy. As a result, new roles have arisen in the form of network governance. These require skills of flexibility, communication, and expectation management, so as to facilitate new forms of governance in less certain conditions. Two contrasting case studies illustrate tensions and dilemmas that arise.
Paul and Reception History
Authors: Riches John
Published: July 2019

This chapter considers currently held views about the history of Pauline interpretation with their strong critique of Lutheran readings of Paul and attempts to locate Lutheran readings more fully within the wider history of Pauline interpretation. It pays particular attention to the work of Marcion, Chrysostom, Augustine, Aquinas, Luther, and Calvin. It seeks to show how each new interpreter interacts with earlier readings and brings in other aspects of the text which enable him to confront contemporary issues in his reading community. As such, the reception history of the Pauline letters sheds light on the process whereby the letters themselves came into being as Paul’s readers reacted to his utterances, verbal and written, and Paul responded.
A Review of Lumbar Spinal Stenosis with Intermittent Neurogenic Claudication: Disease and Diagnosis
Authors: Deer Timothy , Sayed Dawood , Michels John , Josephson Youssef , Li Sean , Calodney Aaron K
Published: July 2019

Objective

Lumbar spinal stenosis (LSS) is a degenerative spinal condition affecting nearly 50% of patients presenting with lower back pain. The goal of this review is to present and summarize the current data on how LSS presents in various populations, how it is diagnosed, and current therapeutic strategies. Properly understanding the prevalence, presentation, and treatment options for individuals suffering from LSS is critical to providing patients the best possible care.

Results

The occurrence of LSS is associated with advanced age. In elderly patients, LSS can be challenging to identify due to the wide variety of presentation subtleties and common comorbidities such as degenerative disc disease. Recent developments in imaging techniques can be useful in accurately identifying the precise location of the spinal compression. Treatment options can range from conservative to surgical, with the latter being reserved for when patients have neurological compromise or conservative measures have failed. Once warranted, there are several surgical techniques at the physician’s disposal to best treat each individual case.
Review of Knee Joint Innervation: Implications for Diagnostic Blocks and Radiofrequency Ablation
Authors: Roberts Shannon L , Stout Alison , Dreyfuss Paul
Published: July 2019

Objective

To determine if commonly used knee radiofrequency ablation (RFA) techniques would be able to completely denervate the knee joint.

Methods

A comprehensive search of the literature on knee joint innervation was conducted using the databases Medline, Embase, and PubMed from inception through February 1, 2019. Google Scholar was also searched. Data on the origin, number of articular branches, course, distribution, and frequency of each nerve innervating the knee joint were extracted from the included studies and compared in order to identify variations.

Results

Twelve studies of anterior knee joint innervation and six studies of posterior knee joint innervation were included. The anterior knee joint was innervated by 10 nerves and further subdivided into two parts (anteromedial and anterolateral) or four quadrants (superomedial, inferomedial, superolateral, and inferolateral) based on innervation patterns; the posterior knee joint was innervated by two or three nerves, most commonly via the popliteal plexus. There is a lack of precise, validated anatomic targets identifiable with fluoroscopy and ultrasound for knee diagnostic blocks and RFA. Only three of the 12 or potentially 13 nerves innervating the knee joint are targeted by commonly used knee RFA techniques.

Conclusions

Commonly used knee RFA techniques would not be able to completely denervate the knee joint. It may not be necessary to capture all of the nerves, but only the nerves mediating a patient’s pain. Further clinical studies are required to validate specific diagnostic blocks and evaluate clinical outcomes using rigorous diagnostic blocks and anatomically specific knee RFA techniques.
Treatment of Mixed Azo Dyes in an Aerobic Sequential Batch Reactor and Toxicity Assessment using Vigna radiata
Authors: Vidhya T Akshaya , Gayathri K Veena , Kathawala Tasneem M
Published: July 2019

Azo dyes are the most widely used dyes in the textile industry due to their stability buttheir redundancy to degradation is of major concern, particularly to aquatic ecosystems.Unbound dye is let out in the effluent which not only adds to pollution but its toxic metabolites are known to be carcinogenic leading to severe cases of disease. Biological degradation and toxicity removal has been shown to be an easy and effective process for treating textile effluents. In the present study, a laboratory scale aerobic sequential batch reactor (SBR) was designed and operated for the analysis of degradation of mixed reactive azo dyes. Biological degradation was carried out by activated sludge process at an alkaline pH (8.5). Reactive Brown, Reactive Black and Reactive Red dyes were used in the study at a concentration of 100, 500 and 1000 mg/L in synthetic waste water. The effect of increasing dye concentration on the decolorization efficiency, COD and BOD removal along with chloride, hardness, TDS, MLSS and MLVSS was monitored. The COD removal increased from 34% to 61.15% and then dropped to 21.16% at the highest used concentration. The BOD removal decreased from 63% to 55.55% to 28.14% with increasing dye concentration. In order to remove the residual dye from the effluent, a biosorption experiment was also conducted using dried activated sludge (DAS). The DAS successfully removed more than 0.300 mg of dyes by absorption within 2 hours. A toxicity assessment was carried out by mean of a phytotoxicity test on Vigna radiate where the percentage of germination was used to detect toxic effects of untreated dye containing wastewater on plant growth. The treated wastewater showed 100% germination compared to 70% in untreated wastewater containing 100 mg/L mixed dyes confirming the efficacy of the treatment.
Evaluation of domain adaptation approaches for robust classification of heterogeneous biological data sets
Authors: Schneider Michael , Wang Lichao , Marr Carsten
Published: July 2019

Most machine learning algorithms require that training data are identically distributed to ensure effective learning. In biological studies, however, even small variations in the experimental setup can lead to substantial deviations. Domain adaptation offers tools to deal with this problem. It is particularly useful for cases where only a small amount of training data is available in the domain of interest, while a large amount of training data is available in a different, but relevant domain.

We investigated to what extent domain adaptation was able to improve prediction accuracy for complex biological data. To that end, we used simulated data and time-lapse movies of differentiating blood stem cells in different cell cycle stages from multiple experiments and compared three commonly used domain adaptation approaches. EasyAdapt, a simple technique of structured pooling of related data sets, was able to improve accuracy when classifying the simulated data and cell cycle stages from microscopic images. Meanwhile, the technique proved robust to the potential negative impact on the classification accuracy that is common in other techniques that build models with heterogeneous data. Despite its implementation simplicity, EasyAdapt consistently produced more accurate predictions compared to conventional techniques.

Domain adaptation is therefore able to substantially reduce the amount of work required to create a large amount of annotated training data in the domain of interest necessary whenever the domain changes even a little, which is common not only in biological experiments, but universally exists in almost all data collection routines.
Community attitudes on genetic research of gender identity, sexual orientation, and mental health
Authors: Thomas Taylor R. , Hofammann Dabney , McKenna Brooke G. , van der Miesen Anna I.R. , Stokes Mark A. , Daniolos Peter , Michaelson Jacob J.
Published: July 2019

Biological sex is an important factor in mental health, and a non-binary view of how variation in sex and gender influence mental health represents a new research frontier that may yield new insights. The recent acceleration of research into sexual orientation, gender identity, and mental health has generally been conducted without sufficient understanding of the opinions of sexual and gender minorities (SGM) toward this research. We surveyed 768 individuals, with an enrichment of LGBTQ+ stakeholders, for their opinions regarding genetic research of SGM and mental health. We found that the key predictors of attitudes toward genetic research specifically on SGM are 1) general attitudes toward genetic and mental health research 2) tolerance of SGM and associated behaviors 3) non-cisgender stakeholder status and 4) age of the respondent. Non-heterosexual stakeholder status was significantly associated with increased willingness to participate in genetic research if a biological basis for gender identity were discovered. We also found that non-stakeholders with a low tolerance for SGM indicated their SGM views would be positively updated if science showed a biological basis for their behaviors and identities. These findings represent an important first step in understanding and engaging the LGBTQ+ stakeholder community in the context of genetic research.
TRIBES: A user-friendly pipeline for relatedness detection and disease gene discovery
Authors: Twine Natalie A. , Szul Piotr , Henden Lyndal , McCann Emily P. , Blair Ian P. , Williams Kelly L. , Bauer Denis C.
Published: July 2019

TRIBES is a user-friendly pipeline for relatedness detection in genomic data. TRIBES is the first tool which is both accurate up to 7th degree relatives (e.g. third cousins) and combines essential data processing steps into a single user-friendly pipeline. Furthermore, using a proof-of-principle cohort comprising amyotrophic lateral sclerosis cases with known relationship structures and a known causal mutation in SOD1, we demonstrated that TRIBES can successfully uncover disease susceptibility loci. TRIBES has multiple applications in addition to disease gene mapping, including sample quality control in genome wide association studies and avoiding consanguineous unions in family planning.

Availability

TRIBES is freely available on GitHub: https://github.com/aehrc/TRIBES/

Contact

natalie.twine@csiro.au

Supplementary information

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Independent evolution of polymerization in the Actin ATPase clan regulates hexokinase activity
Authors: Stoddard Patrick R , Lynch Eric M. , Farrell Daniel P. , Justman Quincey A. , Dosey Annie M. , DiMaio Frank , Williams Tom A. , Kollman Justin M. , Murray Andrew W. , Garner Ethan C.
Published: July 2019

The actin protein fold is found in cytoskeletal polymers, chaperones, and various metabolic enzymes. Many actin-fold proteins, like the carbohydrate kinases, do not polymerize. We find that Glk1, aSaccharomyces cerevisiaeglucokinase, forms two-stranded filaments with unique ultrastructure, distinct from that of cytoskeletal polymers. In cells, Glk1 polymerizes upon sugar addition and depolymerizes upon sugar withdrawal. Glk1 polymerization inhibits its enzymatic activity, thus the Glk1 monomer-polymer equilibrium sets a maximum rate of glucose phosphorylation regardless of Glk1 concentration. A mutation eliminating Glk1 polymerization alleviates concentration-dependent enzyme inhibition, causing glucokinase activity to become unconstrained. Polymerization-based regulation of Glk1 activity serves an important functionin vivo: yeast containing non-polymerizing Glk1 are less fit when growing on sugars and more likely to die when refed glucose. Glucokinase polymerization arose within the ascomycete fungi and is conserved across a group of divergent (150-200 mya) yeast. We show that Glk1 polymerization arose independently from other actin-related filaments and allows yeast to rapidly modulate glucokinase activity as nutrient availability changes.

One-sentence summary

Yeast glucokinase activity is limited by its polymerization, which is critical for cell viability during glucose refeeding.
Impact of Měnglà virus proteins on human and bat innate immune pathways
Authors: Williams Caroline G. , Gibbons Joyce Sweeney , Keiffer Timothy R. , Luthra Priya , Edwards Megan R. , Basler Christopher F.
Published: July 2019

Měnglà virus (MLAV), identified inRousettusbats, is a phylogenetically distinct member of the familyFiloviridae. Because filoviruses Ebola virus (EBOV) and Marburg virus (MARV) modulate host innate immune pathways, MLAV VP35, VP40 and VP24 proteins were compared with their EBOV and MARV homologs for innate immune pathway modulation. In human andRousettuscells, MLAV VP35 behaved like EBOV and MARV VP35s, inhibiting virus-induced activation of the interferon (IFN)-β promoter. MLAV VP35 inhibited IRF3 phosphorylation and interacted with PACT, a host protein engaged by EBOV VP35 to inhibit RIG-I signaling. MLAV VP35 also inhibited PKR activation. MLAV VP40 was demonstrated to inhibit type I IFN induced gene expression in human and bat cells. It blocked STAT1 tyrosine phosphorylation induced either by type I IFN or over-expressed Jak1, paralleling MARV VP40. MLAV VP40 also inhibited virus-induced IFNβ promoter activation, a property shared by MARV VP40 and EBOV VP24. The inhibition of IFN induction was preserved in the presence of a Jak kinase inhibitor, demonstrating that inhibition of Jak-STAT signaling is not sufficient to explain inhibition of IFNβ promoter activation. MLAV VP24 did not inhibit IFN-induced gene expression or bind karyopherin α5, properties of EBOV VP24. MLAV VP24 also differed from MARV VP24 in that it failed to interact with Keap1 or activate an antioxidant response element reporter gene, due to the absence of a Keap1-binding motif. These studies demonstrate similarities between MLAV and MARV in how they suppress IFN responses and differences in how MLAV VP24 interacts with host pathways.

Importance

EBOV and MARV, members of the familyFiloviridae, are highly pathogenic zoonotic viruses that cause severe disease in humans. Both viruses use several mechanisms to modulate the host innate immune response, and these likely contribute to severity of disease. Here, we demonstrate that MLAV, a filovirus newly discovered in a bat, suppresses antiviral type I interferon responses in both human and bat cells. Inhibitory activities are possessed by MLAV VP35 and VP40, which parallels how MARV blocks IFN responses. However, whereas MARV activates cellular antioxidant responses through an interaction between its VP24 protein and host protein Keap1, MLAV VP24 lacks a Keap1 binding motif and fails to activate this cytoprotective response. These data indicate that MLAV possesses immune suppressing functions that could facilitate human infection. They also demonstrate key differences in MLAV versus either EBOV or MARV engagement of host signaling pathways.
Exploitation of local and global information in predictive processing
Authors: Kluger Daniel S. , Broers Nico , Roehe Marlen A. , Wurm Moritz F. , Busch Niko A. , Schubotz Ricarda I.
Published: July 2019

While prediction errors have been established to instigate learning through model adaptation, recent studies have stressed the role of model-compliant events in predictive processing. Specifically, so-called checkpoints have been suggested to be sampled for model evaluation, particularly in uncertain contexts.

Using electroencephalography (EEG), the present study aimed to investigate the interplay of such global information and local adjustment cues prompting on-line adjustments of expectations. Within a stream of single digits, participants were to detect ordered sequences (i.e., 3-4-5-6-7) that had a regular length of five digits and were occasionally extended to seven digits. Across experimental blocks, these extensions were either rare (low irreducible uncertainty) or frequent (high uncertainty) and could be unexpected or indicated by incidental colour cues.

Exploitation of local cue information was reflected in significant decoding of cues vs non-informative analogues using multivariate pattern classification. Modulation of checkpoint processing as a function of global uncertainty was likewise reflected in significant decoding of high vs low uncertainty checkpoints. In line with previous results, both analyses comprised the P3b time frame as an index of excess model-compliant information sampled from probabilistic events.

Accounting for cue information, an N400 component was revealed as the correlate of locally unexpected (vs expected) outcomes, reflecting effortful integration of incongruous information. Finally, we compared the fit of a global model (disregarding local adjustments) and a local model (including local adjustments) using representational similarity analysis (RSA). RSA revealed a better fit for the global model, underscoring the precedence of global reference frames in hierarchical predictive processing.
An ultrasensitive fiveplex activity assay for cellular kinases
Authors: Smolko Christian M. , Janes Kevin A.
Published: July 2019

Protein kinases are enzymes whose abundance, protein-protein interactions, and posttranslational modifications together determine net signaling activity in cells. Large-scale data on cellular kinase activity are limited, because existing assays are cumbersome, poorly sensitive, low throughput, and restricted to measuring one kinase at a time. Here, we surmount the conventional hurdles of activity measurement with a multiplexing approach that leverages the selectivity of individual kinase-substrate pairs. We demonstrate proof of concept by designing an assay that jointly measures activity of five pleiotropic signaling kinases: Akt, IκB kinase (IKK), c-jun N-terminal kinase (JNK), mitogen-activated protein kinase (MAPK)-extracellular regulated kinase kinase (MEK), and MAPK-activated protein kinase-2 (MK2). The assay operates in a 96-well format and specifically measures endogenous kinase activation with coefficients of variation less than 20%. Multiplex tracking of kinase-substrate pairs reduces input requirements by 25-fold, with ~75 μg of cellular extract sufficient for fiveplex activity profiling. We applied the assay to monitor kinase signaling during coxsackievirus B3 infection of two different host-cell types and identified multiple differences in pathway dynamics and coordination that warrant future study. Because the Akt–IKK–JNK–MEK–MK2 pathways regulate many important cellular functions, the fiveplex assay should find applications in inflammation, environmental-stress, and cancer research.
Detecting GPCR Complexes in Postmortem Human Brain with Proximity Ligation Assay and A Bayesian Classifier
Authors: Zhu Ying , Mészáros József , Walle Roman , Fan Rongxi , Sun Ziyi , Dwork Andrew J. , Trifilieff Pierre , Javitch Jonathan A.
Published: July 2019

Despite the general controversy regarding the existence and physiological relevance of Class A GPCR dimerization, there is substantial evidence for functional interactions between dopamine D2 receptor (D2R) and adenosine A2A receptor (A2AR). A2AR-D2R complexes have been detected in rodent brains by proximity ligation assay (PLA), but their existence in the human brain is yet to be demonstrated. In this study, we used brightfield PLA, combined with a systematic sampling and a parameter-free naïve Bayesian classifier, and demonstrated proximity between D2R and A2AR in the adult human ventral striatum, consistent with their colocalization within complexes and the possible existence of D2R-A2AR heteromers. These methods are applicable to the quantitative analysis of proximity of two proteins and the expression of individual proteins.

Method Summary

Brightfield proximity ligation assay (PLA) was used to assess the expression of G protein-coupled receptors and their proximity in postmortem adult human brains. A novel automated machine learning method (Bayesian Optimized PLA Signal Sorting) was developed to automatically quantify brightfield PLA data.
Histone methyltransferase MMSET/NSD2 is essential for generation of B1 cell compartment in mice
Authors: Dobenecker Marc-Werner , Yurchenko Vyacheslav , Marcello Jonas , Becker Annette , Rudensky Eugene , Bahnu Natarajan V. , Carrol Thomas , Garcia Benjamin A. , Rosenberg Brad R. , Prinjha Rabinder , Tarakhovsky Alexander
Published: July 2019

Humoral immunity in mice and man relies on the function of two developmentally and functionally distinct B cell subsets - B1 and B2 cells. While B2 cells are responsible for most of the adaptive response to environmental antigens, B1 cells, which are comprised of phenotypically distinct B1a and B1b cells, are carriers of the innate humoral immunity that relies on production of poly-reactive and low affinity antibodies. The molecular mechanism of B cell specification into different subsets is not well established. Here we identified lysine methyltransferase MMSET/NSD2 as a critical regulator of the B1 cell population. We show that NSD2 deficiency in B cell precursors prevents generation of the B1 cell compartment, while having a minor impact on B2 cells. Our data revealed MMSET/NSD2, which catalyzes histone H3 lysine 36 di-methylation, as the first in class epigenetic master regulator of a major B cell lineage in mice.
Exploring Perceptual Illusions in Deep Neural Networks
Authors: Ward Emily J.
Published: July 2019

Perceptual illusions—discrepancies between what exists externally and what we actually see—reveal a great deal about how the perceptual system functions. Rather than failures of perception, illusions expose automatic computations and biases in visual processing that help make better decisions from visual information to achieve our perceptual goals. Recognizing objects is one such perceptual goal that is shared between humans and certain Deep Convolutional Neural Networks, which can reach human-level performance. Do neural networks trained exclusively for object recognition “perceive” visual illusions, simply as a result of solving this one perceptual problem? Here, I showed four classic illusions to humans and a pre-trained neural network to see if the network exhibits similar perceptual biases. I found that deep neural networks trained exclusively for object recognition exhibit the Müller-Lyer illusion, but not other illusions. This result shows that some perceptual computations that are similar to humans’ may come “for free” in a system with perceptual goals similar to humans’.
Systems-level analysis identifies key regulators driving epileptogenesis in temporal lobe epilepsy
Authors: Fu Yingxue , Guo Zihu , Wu Ziyin , Chen Liyang , Ma Yaohua , Wang Zhenzhong , Xiao Wei , Wang Yonghua
Published: July 2019

Temporal lobe epilepsy (TLE) is the most prevalent and often devastating form of epilepsy. The molecular mechanism underlying the development of TLE remains largely unknown, which hinders the discovery of effective anti-epileptogenic drugs. In this study, we built a systems-level analytic framework which integrates gene meta-signatures, gene coexpression network and cellular regulatory network to unveil the evolution landscape of epileptogenic process and to identify key regulators that govern the transition between different epileptogenesis stages. The time-specific hippocampal transcriptomic profiles from five independent rodent TLE models were grouped into acute, latent and chronic stages of epileptogenesis, and were utilized for generating stage-specific gene expression signatures. 13 cell-type specific functional modules were identified from the epilepsy-context coexpression network, and five of them were significantly associated with the entire epileptogenic process. By inferring the differential protein activity of gene regulators in each stage, 265 key regulators underlying epileptogenesis were obtained. Among them, 122 regulators were demonstrated being associated with high seizure frequency and/or hippocampal sclerosis in human TLE patients. Importantly, we discovered four new gene regulators (ANXA5, FAM107A, SEPT2 and SPARC) whose upregulation may drive the process of epileptogenesis and further lead to chronic recurrent seizures or hippocampal sclerosis. Our findings provide a landscape of the gene network dynamics underlying epileptogenesis and uncovered candidate regulators that may serve as potential targets for future anti-epileptogenic therapy development.
Risk of Seizures Induced by Intracranial Research Stimulation: Analysis of 770 Stimulation Sessions
Authors: Goldstein Hannah E. , Smith Elliot H. , Gross Robert E. , Jobst Barbara C. , Lega Bradley C. , Sperling Michael R. , Worrell Gregory A. , Zaghloul Kareem A. , Wanda Paul A. , Kahana Michael J. , Rizzuto Daniel S. , Schevon Catherine A. , McKhann Guy M. , Sheth Sameer A.
Published: July 2019

Background

Patients with medically refractory epilepsy often undergo intracranial electroencephalography (iEEG) monitoring to identify a seizure focus and determine their candidacy for surgical intervention. This clinically necessary monitoring period provides an increasingly utilized research opportunity to study human neurophysiology, however, ethical concerns demand a thorough appreciation of the associated risks.

Objective

We measured the incidence of research stimulation-associated seizures in a large multi-institutional study on brain stimulation’s effect on memory in order to determine if brain stimulation was statistically associated with seizure incidence, and identify potential risk factors for stimulation-associated seizures.

Methods

188 subjects undergoing iEEG monitoring across 10 institutions participated in 770 research stimulation sessions over 3.5 years. Seizures within 30 minutes of a stimulation session were included in our retrospective analysis. We analyzed stimulation parameters, seizure incidence, and typical seizure patterns, to assess the likelihood that recorded seizures were stimulation-induced, rather than events that occurred by chance in epilepsy patients prone to seizing.

Results

In total, 14 seizures were included in our analysis. All events were single seizures, and no adverse events occurred. The mean amplitude of seizure-associated stimulation did not differ significantly from the mean amplitude delivered in sessions without seizures.

In order to determine the likelihood that seizures were stimulation induced, we used three sets of analyses: Visual iEEG analysis, statistical frequency, and power analyses. We determined that three of the 14 seizures were likely stimulation-induced, five were possibly stimulation-induced, and six were unlikely stimulation-induced. Overall, we estimate a rate of stimulation-induced seizures between 0.39% and 1.82% of sessions.

Conclusions

The rarity of stimulation-associated seizures, and that none added morbidity or affected the clinical course of any patient, are important findings for understanding the feasibility and safety of intracranial stimulation for research purposes.
Non-axisymmetric shapes of biological membranes from locally induced curvature
Authors: Omar Yannick A. D. , Sahu Amaresh , Sauer Roger A. , Mandadapu Kranthi K.
Published: July 2019

In various biological processes such as endocytosis and caveolae formation, the cell membrane is locally deformed into curved configurations. Previous theoretical and computational studies to understand membrane morphologies resulting from locally induced curvature are often limited to axisymmetric shapes, which severely restricts the physically admissible morphologies. Under the restriction of axisymmetry, past efforts predict that the cell membrane buds at low resting tensions and stalls at a flat pit at high resting tensions. In this work, we lift the restriction of axisymmetry by employing recent theoretical and numerical advances to understand arbitrarily curved and deforming lipid bilayers. Our non-axisymmetric morphologies reveal membrane morphologies which agree well with axisymmetric studies—however only if the resting tension of the membrane is low. When the resting tension is moderate to high, we show that (i) axisymmetric invaginations are unstable; and (ii) non-axisymmetric ridge-shaped structures are energetically favorable. We further study the dynamical effects resulting from the interplay between intramembrane viscous flow and induced curvature, and find the rate at which the locally induced curvature increases is a key determinant in the formation of ridges. In particular, we show that axisymmetric buds are favored when the induced curvature is rapidly increased, while non-axisymmetric ridges are favored when the curvature is slowly increased: The rate of change of induced curvature affects the intramembrane viscous flow of lipids, which can impede the membrane’s ability to transition into ridges. We conclude that the appearance of non-axisymmetric ridges indicates that axisymmetry cannot be generally assumed when understanding processes involving locally induced curvature. Our results hold potentially relevant implications for biological processes such as endocytosis, and physical phenomena like phase separation in lipid bilayers.
Mebendazole for Differentiation Therapy of Acute Myeloid Leukemia Identified by a Lineage Maturation Index
Authors: Li Yulin , Thomas Daniel , Deutzmann Anja , Majeti Ravindra , Felsher Dean W. , Dill David L.
Published: July 2019

Accurate assessment of changes in cellular differentiation status in response to drug treatments or genetic perturbations is crucial for understanding tumorigenesis and developing novel therapeutics for human cancer. We have developed a novel computational approach, the Lineage Maturation Index (LMI), to define the changes in differentiation state of hematopoietic malignancies based on their gene expression profiles. We have confirmed that the LMI approach can detect known changes of differentiation state in both normal and malignant hematopoietic cells. To discover novel differentiation therapies, we applied this approach to analyze the gene expression profiles of HL-60 leukemia cells treated with a small molecule drug library. Among multiple drugs that significantly increased the LMIs, we identified mebendazole, an anti-helminthic clinically used for decades with no known significant toxicity. We tested the differentiation activity of mebendazole using primary leukemia blast cells isolated from human acute myeloid leukemia (AML) patients. We determined that treatment with mebendazole induces dramatic differentiation of leukemia blast cells as shown by cellular morphology and cell surface markers. Furthermore, mebendazole treatment significantly extended the survival of leukemia-bearing mice in a xenograft model. These findings suggest that mebendazole may be utilized as a low toxicity therapeutic for human acute myeloid leukemia and confirm the LMI approach as a robust tool for the discovery of novel differentiation therapies for cancer.
Independent Control of the Thermodynamic and Kinetic Properties of Aptamer Switches
Authors: Wilson Brandon D. , Hariri Amani A. , Thompson Ian A.P. , Eisenstein Michael , Soh H. Tom
Published: July 2019

Molecular switches that change their conformation upon target binding offer powerful capabilities for biotechnology and synthetic biology. In particular, aptamers have proven useful as molecular switches because they offer excellent binding properties, undergo reversible folding, and can be readily engineered into a wide range of nanostructures. Unfortunately, the thermodynamic and kinetic properties of the aptamer switches developed to date are intrinsically coupled, such that high temporal resolution (i.e., switching time) can only be achieved at the cost of lower sensitivity or high background. Here, we describe a general design strategy that decouples the thermodynamic and kinetic behavior of aptamer switches to achieve independent control of sensitivity and temporal resolution. We used this strategy to generate an array of aptamer switches with effective dissociation constants (KD) ranging from 10 μM to 40 mM and binding kinetics ranging from 170 ms to 3 s—all generated from the same parent ATP aptamer. Our strategy is broadly applicable to other aptamers, enabling the efficient development of switches with characteristics suitable for diverse range of biotechnology applications.