bluuebunny/crossref_metadata_2025 huggingface dataset:
Conclusion
Authors: Moss Jessica
Published: February 2021

My main concern in the book has been to show that Plato’s epistemology is fundamentally different from ours, and to investigate—once freed of the constraints imposed when we try to read him through our own views—just how his epistemology works. Recognizing the differences will however raise an important question: why would Plato do epistemology his way? This chapter provides an answer, in broad strokes. Plato’s philosophy is largely driven by an ethical question: How should one live? His epistemology makes sense as part of his answer. For Plato, especially in the Two Worlds dialogues, the bright line in ethics is between blessed contact with Being and pitiable immersion in seeming. Therefore the bright line in epistemology—the salient division between higher and lower—is the line between accepting what seems as final, and going beyond this to find what Is.
Member States’ Due Diligence Obligations to Supervise International Organisations
Authors: Daugirdas Kristina
Published: February 2021

There are two reasons to consider member states’ obligations to supervise international organisations as a distinct category of due diligence obligations. First, due diligence obligations typically require states to regulate third parties in some way. But it is harder for states to regulate international organisations than other private actors because international law protects the autonomy of international organisations. Second, such due diligence obligations merit attention because they may compensate for the dearth of mechanisms to hold international organisations accountable when they cause harm. This chapter canvasses member states’ existing obligations vis-à-vis international organisations, and argues in particular that the International Law Commission (ILC) missed an opportunity to frame broader obligations when drafting the Articles on the Responsibility of International Organizations (the ARIO). The chapter closes by making the normative case for establishing a due diligence obligation on member states to ensure that international organisations do not abuse their immunities.
Due Diligence and the Duty to Protect Human Rights
Authors: Baade Björnstjern
Published: February 2021

This chapter shows that a state’s duty to protect human rights is an obligation that requires due diligence. As a standard of conduct under international human rights law, due diligence demands balancing a foreseeable risk to a protected interest against countervailing interests. The chapter reviews the practice of human rights courts and treaty bodies, concerning gender-based violence, business activities, official misconduct, and natural hazards. It reveals the way that due diligence requirements are operationalised in practice. The chapter argues that, despite occasional arguments to the contrary, due diligence does not dilute established standards of international human rights law but complements them. It serves to effectively mitigate risks to human rights no matter the risks’ source, in a manner that is also able to address systemic problems.
Due Diligence and the Obligation to Prevent Genocide and Crimes Against Humanity
Authors: van den Herik Larissa , Irving Emma
Published: February 2021

This chapter analyses the due diligence component of the duty to prevent genocide and crimes against humanity. It examines the International Court of Justice (ICJ) judgment in the Bosnia Genocide case of 2007 and outlines the system of differentiated obligations based on a state’s ‘capacity to influence’ events in another state set out in the judgment. Furthermore, the chapter argues that developments under customary international law, which are buttressed and specified by the International Law Commission (ILC), support the existence of an obligation to prevent crimes against humanity of an equivalent character to the obligation to prevent genocide. The chapter examines the role that due diligence plays in delimiting the nature and scope, the content, and the temporal elements of the obligations to prevent genocide and crimes against humanity. Taking a future-oriented approach, the chapter enquires how new technologies inform state’s due diligence and whether non-state actors (including social media companies) can have the necessary ‘capacity to influence’, thus extending the preventive obligation’s potential reach.
Due Diligence Debates in International Anti-corruption and Money Laundering Law
Authors: Ivory Radha
Published: February 2021

This chapter describes and problematises the role of due diligence norms in international anti-corruption and money laundering law. It analyses the international legal framework against the abuse of trust or power for private gain—corruption—and finds that states are obliged to prevent the perpetration or facilitation of such conduct by non-state actors. The chapter demonstrates that, to this end, states must ‘responsibilise’ legal entities and require supervision by those entities of other non-state actors. Both horizontal (state-to-state) and traversal (state-to-business) anti-corruption due diligence obligations are calibrated by discretions and notions of risk. The chapter points out that the international economic crime standards seem to employ a ‘new’ approach to governance or—more problematically—to diffuse ‘new’ forms of ‘penality’ or global governmentality.
Physical spaces and book formats
Authors: Pearson David
Published: February 2021

This chapter provides an overview of our knowledge of ways in which books were stored in homes during the seventeenth century, drawing on existing scholarship and on evidence from contemporary images and archival sources. The evolution of domestic library spaces is considered, and ways in which books were displayed as well as stored. This chapter also discusses the importance of recognizing the cheaper and more temporary formats in which many books were bought and used during this period, using rare surviving concentrations of stitched pamphlets (e.g. at the Plume Library) to supplement the evidence provided by early sale catalogues.
Cultures of collecting
Authors: Pearson David
Published: February 2021

Studies of private libraries and their owners invariably talk about ‘book collecting’—is this the right terminology? After summarizing our broadly held understanding of the evolution of bibliophile collecting from the eighteenth century onwards, this chapter considers the extent to which similar behaviours can be detected (or not) in the seventeenth, drawing on the material evidence of bookbindings, wording in wills, and other sources. Do we find subject-based collecting, of the kind we are familiar with today, as a characteristic of early modern book owners? Some distinctions are recognized in ways in which medieval manuscripts (as opposed to printed books) were brought together at this time. The relationship between libraries and museums, and contemporary attitudes to them, is explored. The concluding argument is that ‘collecting’ is a careless word to use in the seventeenth-century context; just as we should talk about users rather than readers, we should use ‘owners’ rather than ‘collectors’ as the default term, unless there is evidence to the contrary.
Brain Computations
Authors: Rolls Edmund T.
Published: February 2021

The subject of this book is how the brain works. In order to understand this, it is essential to know what is computed by different brain systems; and how the computations are performed. The aim of this book is to elucidate what is computed in different brain systems; and to describe current computational approaches and models of how each of these brain systems computes. Understanding the brain in this way has enormous potential for understanding ourselves better in health and in disease. Potential applications of this understanding are to the treatment of the brain in disease; and to artificial intelligence which will benefit from knowledge of how the brain performs many of its extraordinarily impressive functions. This book is pioneering in taking this approach to brain function: to consider what is computed by many of our brain systems; and how it is computed. The book will be of interest to all scientists interested in brain function and how the brain works, whether they are from neuroscience, or from medical sciences including neurology and psychiatry, or from the area of computational science including machine learning and artificial intelligence, or from areas such as theoretical physics.
The taste and flavour system
Authors: Rolls Edmund T.
Published: February 2021

Information is represented in taste regions up to and including the insular primary taste system of what the taste is independent of its reward value and pleasantness with a sparse distributed representation of sweet, salt, bitter, sour and umami inputs. The texture of food in the mouth, including fat texture, is also represented in these areas. The insular taste cortex then projects to the orbitofrontal cortex, in which the reward value and pleasantness of the taste and flavour are represented, with olfactory components included.
The olfactory system
Authors: Rolls Edmund T.
Published: February 2021

There are 1000 gene-specified olfactory receptor types projecting to the olfactory bulb and then to the olfactory (pyriform) cortex. This processing enables what the odour is to be represented. The olfactory (pyriform) cortex then projects to the orbitofrontal cortex, where the representation is mapped away from a gene-specified space into an odour reward value space, with the orbitofrontal cortex responding for example to the pleasantness of odours including the smell and flavour of food. The mechanism of the transform includes pattern association with stimuli in other modalities, such as the taste and texture of food.
The auditory system
Authors: Rolls Edmund T.
Published: February 2021

Mechanisms for left-right auditory localization involving time differences for low frequencies, and intensity differences for high frequencies, performed in the brainstem are described. Auditory localization in 3D space using the pinna as an asymmetrical antenna is described. The auditory cortical areas in the superior temporal gyrus are hierarchically organised and can detect feature combinations. Auditory neurons in the orbitofrontal cortex and nearby inferior frontal gyrus can respond to vocalizations used in communication; and the human orbitofrontal cortex is involved in identifying the emotional expression in a voice, which is useful in social behaviour.
The parietal cortex, spatial functions, and navigation
Authors: Rolls Edmund T.
Published: February 2021

The parietal areas that are involved in the dorsal visual stream are described in Chapter 3. This Chapter builds on that, and considers the functions of spatial representations in the parietal cortex and areas to which it projects the retrosplenial and posterior cingulate cortex, which in turn project to the hippocampus, in navigation. It is hypothesized that human navigation is likely to often depend on spatial view neurons, which with a list of landmarks provides a common method of navigation. This may be complemented by the use of allocentric bearing to a landmark cells, which provide a basis for navigation that is not based on approach to landmarks, but instead on bearings to landmarks. Models for both types of navigation are provided with Matlab code. Idiothetic (self-motion) update of hippocampal representations is likely to be performed by the operations of the coordinate transform systems in the dorsal visual system described in Chapter 3, which provides inputs to the hippocampus.
The cingulate cortex
Authors: Rolls Edmund T.
Published: February 2021

The cingulate cortex is involved in action-outcome learning. The concept is that posterior cingulate cortex action-related information received from the parietal cortex is brought together in the cingulate cortex with the anterior cingulate cortex reward outcome-related information received from the orbitofrontal cortex, and via the midcingulate cortex the result of action-outcome learning can influence premotor areas. In addition, the posterior cingulate cortex has major connectivity with the parahippocampal cortex, which in turn projects spatial information to the entorhinal cortex and thereby into the hippocampal episodic memory system. The posterior cingulate cortex thus provides a route for spatial including visuo-spatial information to reach the hippocampus, where it can be combined with object and reward-related information to form episodic memories.
The Tricategory of Bicategories
Authors: Johnson Niles , Yau Donald
Published: February 2021

In this chapter, the tricategory of bicategories is presented in full detail. After a preliminary discussion of the whiskerings of a lax transformation with a lax functor, the chapter goes on to define a tricategory. The rest of the chapter proves in detail the existence of a tricategory with small bicategories as objects (i.e. a tricategory of bicategories), pseudofunctors as 1-cells, strong transformations as 2-cells, and modifications as 3-cells.
Vocal Repertoire for the Twenty-First Century, Volume 2
Authors: Manning Jane
Published: February 2021

In this new follow-up to her highly regarded New Vocal Repertory, volumes 1 and 2, English concert and opera soprano Jane Manning provides a seasoned expert’s guidance and insight into the vocal genre she calls home. Manning’s comprehensive selection of contemporary art songs in Vocal Repertoire for the Twenty-First Century ranges from the avant-garde to the more easily accessible, including substantial song cycles, shorter encore pieces, and songs suitable for auditions and competitions. Each of the selections is accompanied by a highly detailed performance guide, music examples, levels of difficulty, and a brief encapsulation of vocal characteristics or challenges contained in the piece. A supplemental companion website provides composer biographies and an up-to-date list of recommended recordings. With a focus on younger composers in addition to prominent figures, Manning encourages singers to refresh and expand their recital repertoire into less familiar territory, and discover the rewards therein.
MICHAEL BERKELEY (b. 1948)Three Songs to Children (2002)
Authors: Manning Jane
Published: February 2021

This chapter looks at British composer Michael Berkeley’s Three Songs to Children (2002). This early piece, recently revised, is ideal for a young artist’s recital. Unpretentious and straightforward in its demands, it has a haunting charm and freshness. In addition to higher voices, a light mezzo could sing it comfortably, since there are no extremes of tessitura. The individual essence of three great but fundamentally different poets is mirrored in the contrasting treatment of the settings. The first—‘A Cradle Song’ (W. B. Yeats)—is a tender, rocking lullaby; the central, longest song—‘Sonnet to a Child’ (Wilfred Owen)—digs deeper, capturing the vibrant imagery and poignant reflections in more rhetorical style; and the third—‘A Child Asleep’ (Walter de la Mare)—is bound together by a continuous running accompaniment. The composer favours a tonal idiom, sometimes modal, and shows a predilection for sudden key shifts. Cues and doublings in the accompaniment are generally helpful. The lithe vocal lines move easily over a wide range and phrasing is well thought out, but there are a few unexpected quirks in syllabic groupings, including changes of accent and syncopation, which give added life to the rhythms.
JEREMY DALE ROBERTS (1934–2017)Spoken to a Bronze Head (2008)
Authors: Manning Jane
Published: February 2021

This chapter describes British composer Jeremy Dale Roberts’s Spoken to a Bronze Head (2008). This moving song is commissioned for a special celebratory album of settings of poems by Ursula Vaughan Williams. It is an object lesson in skill and economy, and subtly captures the rarefied atmosphere of ancient culture implicit in the text, while demonstrating an assured expressive range. The flexible musical idiom is an attractive mix of the old and the new. Carefully moulded vocal phrases, glowing with natural colours, mirror the stresses of the words and are complemented and supported by a resonant piano part, with slow, full chords redolent of ritual. Meticulous attention to balance and the tiniest nuances of accent and dynamic ensure verbal clarity throughout. The piece will suit a warm-toned singer, possessing a secure low B flat, yet able to pare down vibrato to achieve some clean-edged parlando.
ANTHONY GILBERT (b. 1934)Peace Notes (2011)
Authors: Manning Jane
Published: February 2021

This chapter explores Anthony Gilbert’s Peace Notes (2011), a highly original and fascinating seven-movement cycle. The evocative poems by Sarah Day, full of colourful imagery and alliterative syllables, are ideally suited to detailed treatment, and Gilbert crafts the vocal lines with consummate care, incorporating some characterful ornamentation. Brief, exposed fragments contrast with longer, arching spans, and the writing becomes a little more demanding as the piece progresses. Preparatory work is essential; some rhythms, carefully honed to fit the words, could seem elusive at first, but a dedicated singer should enjoy mastering their subtleties. Extremes of tessitura are largely avoided, but Songs 3–6 (‘Iris’, ‘Margin’, ‘Piano’, and ‘Enrapt’) have some sustained passages that occasionally leave the singer suspended on a high pitch—something that heavier voices may find difficult. The piano writing is relatively unchallenging: lean, uncluttered, and lucid, apart from occasional trills. It supports and enriches the voice part but never drowns it, leaving the singer free to place and manipulate phrases without feeling harried. Dynamics are typically refined and meaningful, affecting vocal and pianistic timbres.
KENNETH HESKETH (b. 1968)Chronicles of the Time (Lamentations from ‘Macbeth’) (2012)
Authors: Manning Jane
Published: February 2021

This chapter discusses British composer Kenneth Hesketh’s Chronicles of the Time (Lamentations from ‘Macbeth’) (2012). This work, showing Hesketh’s understanding of the voice, is an exciting and rewarding vehicle for a baritone with dramatic gifts, one able to achieve a rich palette of moods, colours, and gestures without resorting to extremes of range. Hesketh has assembled a mosaic of texts from Macbeth for his purpose, not ordering them consecutively according to their positions in the play, but constructing a cohesive pattern, with a violent outburst and shorter pithy declamations framed by more prolonged musings on impending death. The piano writing is full of contrast, pungent and volatile; the two performers are very much equal partners, but balance and audibility of text should be no problem, since the composer adopts the ‘classic’ mode of keeping the most volatile pianistic activity to moments when the singer is either sustaining a note or absent altogether. It has to be admitted that, with such free atonality, the singer’s musicianship will be tested and pitching is not easy, but many notes recur so often that ‘muscle memory’ should come into play, and there are many cues in the piano part.
ELAINE HUGH-JONES (b. 1927)Two Night Songs (2000/2001)
Authors: Manning Jane
Published: February 2021

This chapter looks at Elaine Hugh-Jones’s Two Night Songs (2000/2001). These two particular settings (‘The Starlight Night’ and ‘The Nightingale Near the House’) suit the bright resonances of the soprano voice so perfectly that it would be difficult to imagine them transposed. Stylistically, the music is reminiscent of the English Romantics and their successors, but always sounds fresh and personal. It flows spontaneously and elegantly and never loses momentum. The composer’s histrionic gifts make her acutely responsive to poetry. She chooses her texts with unerring taste and sets them immaculately, with careful attention to details such as accents and fluctuating dynamics. The use of subtle rubato is always implied, giving time to savour sensuous harmonic changes and freedom to obey dramatic and expressive impulses without disturbing the flow.
LOWELL LIEBERMANN (b. 1961)Six Songs on Poems of Raymond Carver (2002)
Authors: Manning Jane
Published: February 2021

This chapter examines Lowell Liebermann’s Six Songs on Poems of Raymond Carver (2002). This exciting cycle requires a proficient and polished singer/pianist team. Vocal technique and musicianship will certainly be fully exercised; the songs are satisfyingly meaty, oozing with vitality and assurance. The vividly idiomatic piano writing is a test of stamina and concentration, and balance between voice and keyboard is a crucial issue. Bracingly memorable texts contain much sardonic, dark humour, tempered by passages of touching tenderness. Elements of pastiche, including ‘neoclassical’ runs and repeated rhythmic figures, are successfully incorporated—the fourth song even emulates a decorative Arabic monody. Some extremes of range may tax a young, inexperienced singer, but the cycle should make a tremendous impact in performance.
TOD MACHOVER (b. 1953)Open Up the House (2012)
Authors: Manning Jane
Published: February 2021

This chapter assesses Tod Machover’s Open Up the House (2012). Machover has long been recognized internationally as an outstanding and influential all-round musician and polymath, whose areas of expertise comfortably straddle the twin worlds of arts and science. Most readily associated with groundbreaking innovation in musical technology—often applied to ambitious operatic, educational, and symphonic ventures—he is nonetheless able to tailor his talents to embrace more modest, small-scale forces, as shown here. This exhilarating little piece fizzes with vitality from the outset. The piano’s continual, pulsing, eighth-note chords drive the music along, ensuring that momentum never flags. The incisive soprano writing calls upon the singer’s brightest, most radiant resonances. The piece builds cumulatively, with leaping, plunging intervals, spiked accents, and insistent repetitions. The singer must conserve stamina for the long notes at the ends of phrases, and plan breath spans accordingly.
MISSY MAZZOLI (b. 1980)As Long As We Live (2013)
Authors: Manning Jane
Published: February 2021

This chapter describes American composer Missy Mazzoli’s As Long As We Live (2013). Showing the influence of figures such as the Dutch composer Louis Andriessen as well as some of those involved in the worldwide Bang-on-a-Can movement, this work, which is also available in a version for baritone, could just as easily fit a club setting or popular concert as a more formal recital venue. In order to alleviate balance problems, the singer could be amplified if need be. It is even possible that singer and pianist could be the same person, a situation more frequently found in ‘pop’ concerts. The straightforward appeal and seductively euphonious harmonies of this extended song conceal considerable artistic acumen and an acute ear for subtleties of timbre. Both the simplicity of the vocal line and the characteristically repetitive nature of the piano writing are deceptive. A classically trained singer with a well-centred purity of tone and a firm middle register is surely essential to achieve the pinpoint tuning of intervals, many of which are quite close and clash with the piano’s triadic harmonies.
EDWARD NESBIT (b. 1986)A Pretence of Wit (2010; rev. 2012)
Authors: Manning Jane
Published: February 2021

This chapter examines British composer Edward Nesbit’s A Pretence of Wit (2010; revised 2012). In this piece, Nesbit has assembled a rich sequence of W. B. Yeats poems that deal with aspects of nature and humanity, and are set with skill and empathy. Wisely, he avoids extremes of vocal range, and contrasts smooth, relatively uncluttered cantabile lines with bursts of fast-moving parlando patterns. The cycle will suit a nimble, bright-voiced soprano—a more dramatic, heavy voice could find the frequent delicate passages difficult to negotiate. Dynamics throughout are used subtly: there are a number of distinctive quirky moments which enliven the articulation of the texts. The elaborate piano parts require a player of fine technique and rhythmic command. Three staves are used at a climactic point in the final movement. Ultimately, achieving rhythmic coordination is probably the most challenging aspect for both performers.
CHARLES SHADLE (b. 1960)The Hills of Dawn (2012)
Authors: Manning Jane
Published: February 2021

This chapter focuses on American composer Charles Shadle’s The Hills of Dawn (2012). This beautifully-written short cycle ought to be snapped up eagerly by young artists in particular. It is a perfect length for a recital. The range is tailored to accommodate a light voice, and occasional deep notes do not require powerful projection. Shadle successfully blends elements of English and American post-Romantic music, with an occasional nudge towards Hindemithian neoclassicism, to forge a thoroughly fresh and engaging personal style. The music flows spontaneously and motivic connections between the songs create a feeling of unity, with the piano’s introductions and postludes helping to establish mood and character. Three short middle movements are framed by more substantial opening and closing songs. Standard notation is employed, without key signatures. In an introductory note, the composer reveals a deep, personal affinity with the texts, which he sets with care and sensitivity. The five chosen poems by Native American poet Alexander Lawrence Posey are assembled ‘to suggest the passage from dawn to dusk on a mid-summer’s day’.
JUDITH WEIR (b. 1954)The Voice of Desire (2003)
Authors: Manning Jane
Published: February 2021

This chapter studies Judith Weir’s The Voice of Desire (2003). Weir’s music is fresh, concise, and instantly recognizable, and it successfully assimilates, within a modern idiom, the elements of traditional music and storytelling which are integral to her artistic persona. The piece sets four poems concerning the ambivalent relationships between birds and humans. As may be expected, bird calls and sounds of nature are illustrated strikingly, especially in the piano part. The selected texts provide plenty of variety in mood and character: the first and third songs are the most substantial, and the last a sublimely simple strophic ‘jingle’ which has to be delivered with understated aplomb. The vocal tessitura stays in a rewarding medium range for the most part, taking advantage of natural resonances that can penetrate the texture with ease and adapt to timbral shadings according to context. Helpful pitch-cues, including unisons, are to be found frequently in the piano part. Although originally written for mezzo, it can also be performed effectively by a counter-tenor.
HUGH WOOD (b. 1932)The Isles of Greece (2007)
Authors: Manning Jane
Published: February 2021

This chapter discusses British composer Hugh Wood’s The Isles of Greece (2007). This cycle, begun some years ago, has been heavily revised and gives a fascinating insight into the composer’s progression from post-Schoenbergian modernism into a new vein of sensuous, unabashed romanticism. Each song is distinct in style, but all bear evidence of Wood’s customary attributes of integrity, confident musicality, and refined aural and poetic sensibility. He admits to a deep and abiding affinity with Greece and has assembled an appetizing sequence of poems which convey the vibrant colours and mercurial emotions conjured up by that land. To do justice to the piece, the singer will need a reliable, polished technique. Although medium voice is stipulated, all except the first song are written in the bass clef, and a lightish baritone would seem to be ideal. Dynamic details are a crucial factor, and must be closely observed. Idiomatic piano writing, freely expressive and satisfyingly varied, makes a major contribution.
Comparative Reflections on COVID-19 Responses: Drafting, Powers, and Interpretation
Authors: Yeon Thomas
Published: February 2021

This article examines comparatively approaches in Hong Kong and English law on powers created by the use of subordinate legislations to combat the COVID-19 pandemic from the perspectives of legislative drafting and statutory interpretation. These powers, being wide and flexible in nature, pose a tension between two competing concerns. On the one hand, they enable law enforcement officers to be able to deal with the unique challenges posed by a public health crisis. On the other hand, they pose the potential to restrict fundamental human rights disproportionately. This article will proceed in three parts. First, the article will analyse the responsibilities of drafters in drafting subordinate legislations and the techniques therein; the discussion will be contextualized within a need for urgent public health responses to combat the pandemic. Second, the powers conferred upon law enforcement officers and restrictions on individual liberty under Hong Kong law and English law will be analysed. Third, approaches to interpreting the relevant legislations under the two jurisdictions will be examined. It will be argued that despite the need to confer wide and flexible powers to the executive to combat the pandemic, specificity of language and precision in articulating these powers remain of cardinal and overarching importance.
Investigating the Distribution of Strains of Erwinia amylovora and Streptomycin Resistance in Apple Orchards in New York Using Clustered Regularly Interspaced Short Palindromic Repeat Profiles: A 6-Year Follow-Up
Authors: Wallis Anna , Yannuzzi Isabella M. , Choi Mei-Wah , Spafford John , Fenn Matthew , Ramachandran Padmini , Timme Ruth , Pettengill James B. , Cagle Robin , Ottesen Andrea , Cox Kerik D.
Published: February 2021

Fire blight, caused by the bacterium Erwinia amylovora, is one of the most important diseases of apple. The antibiotic streptomycin is routinely used in the commercial apple industries of New York (NY) and New England to manage the disease. In 2002 and again, from 2011 to 2014, outbreaks of streptomycin resistance (SmR) were reported and investigated in NY. Motivated by new grower reports of control failures, we conducted a follow-up investigation of the distribution of SmR and E. amylovora strains for major apple production regions of NY over the last 6 years (2015 to 2020). Characterization of clustered regularly interspaced short palindromic repeat (CRISPR) profiles revealed that a few “cosmopolitan” strains were widely prevalent across regions, whereas many other “resident” strains were confined to one location. In addition, we uncovered novel CRISPR profile diversity in all investigated regions. SmR E. amylovora was detected only in a small area spanning two counties from 2017 to 2020 and was always associated with one CRISPR profile (41:23:38), which matched the profile of SmR E. amylovora, discovered in 2002. This suggests the original SmR E. amylovora was never fully eradicated and went undetected because of several seasons of low disease pressure in this region. Investigation of several representative isolates under controlled greenhouse conditions indicated significant differences in aggressiveness on ‘Gala’ apples. Potential implications of strain differences include the propensity of strains to become distributed across wide geographic regions and associated resistance management practices. Results from this work will directly influence sustainable fire blight management recommendations for commercial apple industries in NY state and other regions.
IdeTo: Spreadsheets for Calculation and Analysis of Area Under the Disease Progress Over Time Data
Authors: Simko Ivan
Published: February 2021

When disease ratings are obtained over time, area under the disease progress metrics such as area under the disease progress curve (AUDPC) and area under the disease progress stairs (AUDPS), which allow integration of these measures into a single value, have found use for both survey or replicated experiment data. IdeTo, an Excel-based calculator, computes AUDPC, AUDPS, and their standardized and relative values for up to 200 individuals evaluated at 200 timepoints. In addition to the areas, descriptive statistics are provided for the group of individuals (e.g., accessions and replicates), and both Pearson and Spearman correlation coefficients between the areas and other traits of interest. Graphs are provided to visualize the progression of disease scores over time, distribution of AUDPC and AUDPS values in the dataset, and their linear correlation with the traits of interest.

[Formula: see text] The author(s) have dedicated the work to the public domain under the Creative Commons CC0 “No Rights Reserved” license by waiving all of his or her rights to the work worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law, 2021.
Comparative genomics of ST5 and ST30 methicillin-resistant Staphylococcus aureus sequential isolates recovered from paediatric patients with cystic fibrosis
Authors: Haim María Sol , Zaheer Rahat , Bharat Amrita , Di Gregorio Sabrina , Di Conza José , Galanternik Laura , Lubovich Silvina , Golding George R. , Graham Morag R. , Van Domselaar Gary , Cardona Silvia T. , Mollerach Marta
Published: February 2021

Staphylococcus aureus

chronic airway infection in patients with cystic fibrosis (CF) allows this pathogen to adapt over time in response to different selection pressures. We have previously shown that the main sequence types related to community-acquired methicillin-resistant

S. aureus

(MRSA) infections in Argentina – ST5 and ST30 – are also frequently isolated from the sputum of patients with CF, but in these patients they usually display multi-drug antimicrobial resistance. In this study, we sequenced the genomes of MRSA from four paediatric CF patients with the goal of identifying mutations among sequential isolates, especially those possibly related to antimicrobial resistance and virulence, which might contribute to the adaptation of the pathogen in the airways of patients with CF. Our results revealed genetic differences in sequential MRSA strains isolated from patients with CF in both their core and accessory genomes. Although the genetic adaptation of

S. aureus

was distinct in different hosts, we detected independent mutations in thyA, htrA, rpsJ and gyrA – which are known to have crucial roles in

S. aureus

virulence and antimicrobial resistance – in isolates recovered from multiple patients. Moreover, we identified allelic variants that were detected in all of the isolates recovered after a certain time point; these non-synonymous mutations were in genes associated with antimicrobial resistance, virulence, iron scavenging and oxidative stress resistance. In conclusion, our results provide evidence of genetic variability among sequential MRSA isolates that could be implicated in the adaptation of these strains during chronic CF airway infection.
Extreme genetic diversity in the type VII secretion system of Listeria monocytogenes suggests a role in bacterial antagonism
Authors: Bowran Kieran , Palmer Tracy
Published: February 2021

The type VII protein secretion system (T7SS) has been characterized in members of the phyla Actinobacteria and Firmicutes. In mycobacteria the T7SS is intimately linked with pathogenesis and intracellular survival, while in Firmicutes there is mounting evidence that the system plays a key role in interbacterial competition. A conserved membrane-bound ATPase protein, termed EssC in

Staphylococcus aureus

, is a critical component of the T7SS and is the primary receptor for substrate proteins. Genetic diversity in the essC gene of

S. aureus

has previously been reported, resulting in four protein variants that are linked to specific subsets of substrates. Here we have analysed the genetic diversity of the T7SS-encoding genes and substrate proteins across

Listeria monocytogenes

genome sequences. We find that there are seven EssC variants across the species that differ in their C-terminal region; each variant is correlated with a distinct subset of genes for likely substrate and accessory proteins. EssC1 is most common and is exclusively linked with polymorphic toxins harbouring a YeeF domain, whereas EssC5, EssC6 and EssC7 variants all code for an LXG domain protein adjacent to essC. Some essC1 variant strains encode an additional, truncated essC at their T7 gene cluster. The truncated EssC, comprising only the C-terminal half of the protein, matches the sequence of either EssC2, EssC3 or EssC4. In each case the truncated gene directly precedes a cluster of substrate/accessory protein genes acquired from the corresponding strain. Across

L. monocytogenes

strains we identified 40 LXG domain proteins, most of which are encoded at conserved genomic loci. These loci also harbour genes encoding immunity proteins and sometimes additional toxin fragments. Collectively our findings strongly suggest that the T7SS plays an important role in bacterial antagonism in this species.
The Phenome-wide Consequences of Anorexia Nervosa Genes
Authors: Johnson Jessica S. , Cote Alanna C. , Dobbyn Amanda , Sloofman Laura G. , Xu Jiayi , Cotter Liam , Charney Alexander W. ,   Eating Disorders Working Group of the Psychiatric Genomics Consortium, Jordan Jennifer , Kennedy Martin , Landén Mikael , Maguire Sarah L , Martin Nicholas G , Mortensen Preben Bo , Bulik Cynthia M. , Huckins Laura M.
Published: February 2021

Anorexia nervosa (AN) is a psychiatric disorder with complex etiology, with a significant portion of disease risk imparted by genetics. Traditional GWAS studies produce principal evidence for the association of genetic variants with disease, and provide a jumping-off point for downstream functional analyses. Transcriptomic imputation (TI) allows for the translation of SNPs into regulatory mechanisms, which can then be used to assess the functional outcome of genetically regulated gene expression (GReX) in a more broad setting through the use of phenome-wide association studies (PheWAS) in large and diverse clinical biobank populations with electronic health record (EHR) phenotypes. Here, we applied TI using S-PrediXcan to translate the most recent PGC-ED AN GWAS findings into AN-GReX. For significant genes, we imputed AN-GReX in the Mount Sinai BioMe™ Biobank and performed PheWAS on over 2000 clinical outcomes to test the clinical consequences of aberrant expression of these genes. We performed a secondary analysis to assess the impact of BMI on AN-GReX clinical associations.

Our S-PrediXcan analysis identified 47 genes associated with AN, including what is, to our knowledge, the first genetic association of AN with the Major Histocompatibility Complex (MHC). AN-GReX was associated with autoimmune, anthropometric, metabolic, psychiatric and gastrointestinal diagnoses in our biobank cohort, as well as measures of anthropometry, substance use, and pain score. Our analyses reveal that AN-GReX associations with measures of weight and substance use are modified by BMI, and indicate potential avenues of functional mechanism to investigate further.
Optimal Allocation of COVID-19 Vaccines in the Philippines
Authors: Buhat Christian Alvin H. , Lutero Destiny SM. , Olave Yancee H. , Quindala Kemuel M. , Recreo Mary Grace P. , Talabis Dylan Antonio SJ. , Torres Monica C. , Tubay Jerrold M. , Rabajante Jomar F.
Published: February 2021

Vaccine allocation is a national concern especially for countries such as the Philippines that have limited resources in acquiring COVID-19 vaccines. As such, certain groups are suggested to be prioritized for vaccination to protect the most vulnerable before vaccinating others. Our model suggests an allocation of vaccines such that COVID-19 deaths are minimized while the prioritization framework is satisfied. Results of the model show that a vaccine coverage of at least 50 to 70% of the population can be enough for a community with limited supplies, and an increase in vaccine supply is beneficial if initial coverage is less than the specified target range. Also, among the vaccines considered in the study, the one with 89.9% effectiveness and has a 183 Philippine peso (Php) price per dose projected the least number of deaths. Compared to other model variations and common allocation approaches, the model has achieved both an optimal and equitable allocation. This will be helpful for policymakers in determining a vaccine distribution for a resource-constrained community.
Interplay between brassinosteroids and TORC signaling in Arabidopsis revealed by integrated multi-dimensional analysis
Authors: Montes Christian , Liao Ching-Yi , Nolan Trevor M , Song Gaoyuan , Clark Natalie M , Guo Hongqing , Bassham Diane C , Yin Yanhai , Walley Justin W
Published: February 2021

Brassinosteroids (BR) and Target of Rapamycin Complex (TORC) are two major processes coordinating plant growth and stress responses. BRs function through a signaling pathway to extensively regulate gene expression and TORC is known to regulate translation and autophagy. Recent studies revealed that these two pathways crosstalk, but a system-wide view of their interplay is still missing. Thus, we performed transcriptome, proteome, and phosphoproteome profiling of Arabidopsis mutants with altered levels of either BIN2 or RAPTOR1B, two key players in BR and TORC signaling, respectively. We found that perturbation of BIN2 or RAPTOR1B levels affects a common set of gene-products involved in growth and stress responses. Additionally, we performed Multiplexed Assay for Kinase Specificity (MAKS), which provided a system-wide view of direct BIN2 substrates. Furthermore, phosphoproteomic data was used to reconstruct a kinase-signaling network and to identify novel proteins dependent on BR and/or TORC signaling pathways. Loss of function mutants of many of these proteins led to an altered BR response and/or modulated autophagy activity. Altogether, these results provide genome-wide evidence for crosstalk between BR and TORC signaling and established a kinase signaling network that defines the molecular mechanisms of BR and TORC interactions in the regulation of plant growth/stress balance.
Characterization of SARS-CoV-2 genetic structure and infection clusters in a large German city based on integrated genomic surveillance, outbreak analysis, and contact tracing
Authors: Walker Andreas , Houwaart Torsten , Finzer Patrick , Ehlkes Lutz , Tyshaieva Alona , Damagnez Maximilian , Strelow Daniel , Duplessis Ashley , Nicolai Jessica , Wienemann Tobias , Tamayo Teresa , Vasconcelos Malte Kohns , Hülse Lisanna , Hoffmann Katrin , Lübke Nadine , Hauka Sandra , Andree Marcel , Däumer Martin P. , Thielen Alexander , Kolbe-Busch Susanne , Göbels Klaus , Zotz Rainer , Pfeffer Klaus , Timm Jörg , Dilthey Alexander T. ,   German COVID-19 OMICS Initiative (DeCOI)
Published: February 2021

Viral genome sequencing can address key questions about SARS-CoV-2 evolution and viral transmission. Here, we present an integrated system of genomic surveillance in the German city of Düsseldorf, combining a) viral surveillance sequencing, b) genetically based identification of infection clusters in the population, c) analysis of hospital outbreaks, d) integration of public health authority contact tracing data, and e) a user-friendly dashboard application as a central data analysis platform. The generated surveillance sequencing data (n = 320 SARS-CoV-2 genomes) showed that the development of the local viral population structure from August to December 2020 was consistent with European trends, with the notable absence of SARS-CoV-2 variants 20I/501Y.V1/B.1.1.7 and B.1.351 until the end of the local sampling period. Against a background of local surveillance and other publicly available SARS-CoV-2 data, four putative SARS-CoV-2 outbreaks at Düsseldorf University Hospital between October and December 2020 (n = 44 viral genomes) were investigated and confirmed as clonal, contributing to the development of improved infection control and prevention measures. An analysis of the generated surveillance sequencing data with respect to infection clusters in the population based on a greedy clustering algorithm identified five candidate clusters, all of which were subsequently confirmed by the integration of public health authority contact tracing data and shown to be represent transmission settings of particular relevance (schools, care homes). A joint analysis of outbreak and surveillance data identified a potential transmission of an outbreak strain from the local population into the hospital and back; and an in-depth analysis of one population infection cluster combining genetic with contact tracing data enabled the identification of a previously unrecognized population transmission chain involving a martial arts gym. Based on these results and a real-time sequencing experiment in which we demonstrated the feasibility of achieving sample-to-turnaround times of <30 hours with the Oxford Nanopore technology, we discuss the potential benefits of routine ultra-fast sequencing of all detected infections for contact tracing, infection cluster detection, and, ultimately, improved management of the SARS-CoV-2 pandemic.
Structural and functional ramifications of antigenic drift in recent SARS-CoV-2 variants
Authors: Yuan Meng , Huang Deli , Lee Chang-Chun D. , Wu Nicholas C. , Jackson Abigail M. , Zhu Xueyong , Liu Hejun , Peng Linghang , van Gils Marit J. , Sanders Rogier W. , Burton Dennis R. , Reincke S. Momsen , Prüss Harald , Kreye Jakob , Nemazee David , Ward Andrew B. , Wilson Ian A.
Published: February 2021

The protective efficacy of neutralizing antibodies (nAbs) elicited during natural infection with SARS-CoV-2 and by vaccination based on its spike protein has been compromised with emergence of the recent SARS-CoV-2 variants. Residues E484 and K417 in the receptor-binding site (RBS) are both mutated in lineages first described in South Africa (B.1.351) and Brazil (B.1.1.28.1). The nAbs isolated from SARS-CoV-2 patients are preferentially encoded by certain heavy-chain germline genes and the two most frequently elicited antibody families (IGHV3-53/3-66 and IGHV1-2) can each bind the RBS in two different binding modes. However, their binding and neutralization are abrogated by either the E484K or K417N mutation, whereas nAbs to the cross-reactive CR3022 and S309 sites are largely unaffected. This structural and functional analysis illustrates why mutations at E484 and K417 adversely affect major classes of nAbs to SARS-CoV-2 with consequences for next-generation COVID-19 vaccines.
A tissue-aware machine learning framework enhances the mechanistic understanding and genetic diagnosis of Mendelian and rare diseases
Authors: Simonovsky Eyal , Sharon Moran , Ziv Maya , Mauer Omry , Hekselman Idan , Jubran Juman , Vinogradov Ekaterina , Argov Chanan M. , Basha Omer , Kerber Lior , Yogev Yuval , Segrè Ayellet V. , Im Hae Kyung ,   GTEx Consortium, Birk Ohad , Rokach Lior , Yeger-Lotem Esti
Published: February 2021

Genetic studies of Mendelian and rare diseases face the critical challenges of identifying pathogenic gene variants and their modes-of-action. Previous efforts rarely utilized the tissue-selective manifestation of these diseases for their elucidation. Here we introduce an interpretable machine learning (ML) platform that utilizes heterogeneous and large-scale tissue-aware datasets of human genes, and rigorously, concurrently and quantitatively assesses hundreds of candidate mechanisms per disease. The resulting tissue-aware ML platform is applicable in gene-specific, tissue-specific, or patient-specific modes. Application of the platform to selected Mendelian disease genes pinpointed mechanisms that lead to tissue-specific disease manifestation. When applied jointly to diseases that manifest in the same tissue, the models revealed common known and previously underappreciated factors that underlie tissue-selective disease manifestation. Lastly, we harnessed our ML platform toward genetic diagnosis of tissue-selective rare diseases. Patient-specific models of candidate disease-causing genes from 50 patients successfully prioritized the pathogenic gene in 86% of the cases, implying that the tissue-selectivity of rare diseases aids in filtering out unlikely candidate genes. Thus, interpretable tissue-aware ML models can boost mechanistic understanding and genetic diagnosis of tissue-selective heritable diseases. A webserver supporting gene prioritization is available at https://netbio.bgu.ac.il/trace/.