bluuebunny/crossref_metadata_2025 huggingface dataset:
The orbitofrontal cortex, amygdala, reward value, and emotion
Authors: Rolls Edmund T.
Published: February 2021

The orbitofrontal cortex receives from the ends of all sensory processing systems, and converts these representations of what the stimulus is into representations of their reward value. The orbitofrontal cortex is therefore a key brain region in emotions, which can be defined as states elicited by rewards and punishers. Indeed, orbitofrontal cortex activations are linearly related to the subjectively reported pleasantness of stimuli. The orbitofrontal cortex then projects this reward value information to other structures, which implement behavioural output, such as the anterior cingulate cortex, and the basal ganglia. A key computational capacity of the orbitofrontal cortex is one-trial object-reward associations, which are rule-based, and enable primates including humans to change their rewarded behaviour very rapidly. Decision-making using attractor neural networks is described.
DAVID BRUCE (b. 1970)That Time With You (2013)
Authors: Manning Jane
Published: February 2021

This chapter addresses US-born British composer David Bruce’s That Time With You (2013). This impressive cycle retains clear stylistic traces of Bruce’s American heritage. His basic idiom is tonal and strongly grounded, and also contains modal elements. It demands a well-schooled singer with a wide expressive range, stamina, and good breath control. The singer must also be calm and unflappable, so as not to be fazed by the relentlessly fast, irregular rhythmic patterns in the first and third songs. The vocal writing in general is warm, earthy, and womanly. The composer sensibly keeps within the voice’s richest and most rewarding middle range, avoiding extremes. This means that words can be heard easily, and a palette of sensual colours explored. Ultimately, the specially commissioned poems evoke an intuitive response. Bruce sees the cycle as belonging to the tradition of ‘sorrowful songs’ and, of course, the blues. In the first and third settings (‘The Sunset Lawn’ and ‘Black Dress’), the singer is the voice of Death, but in the other two (“That Time with You’ and ‘Bring me Again’), the outpouring of regret is more personal, yet somehow strangely distanced.
DIANA BURRELL (b. 1948)Love Song (with Yoga) (2008)
Authors: Manning Jane
Published: February 2021

This chapter describes Diana Burrell’s Love Song (with Yoga) (2008). A characteristic breath of fresh air, this brief song glories in the physical act of singing, and would make an ideal introduction to a recital, as a robust fanfare. The singer need have no fear of plotting the wide-scattered pitches accurately—an extremely spare piano part traces the vocal line, prompting with subtle cues throughout. Words are set quite high, especially in the first part of the piece, so the singer may need to cover and modify some vowels and keep them open without losing syllabic clarity. There are a good number of quick patterns and short single notes to be flung exuberantly into the air and these must ring out without strain. A naturally high-placed voice should have no difficulty here. The tessitura eventually becomes lower just before the sudden surprise ending.
RICHARD CAUSTON (b. 1971)The Flea (2000)
Authors: Manning Jane
Published: February 2021

This chapter discusses Richard Causton’s The Flea (2000). This is a very different and ostensibly simpler setting of this wonderful text by John Donne from that of Krenek, but one that conveys its wit and sardonic humour with equal effectiveness. Causton, a highly experienced and gifted composer of broad musical tastes, understands the voice very well and has wisely kept to a comfortable tessitura to allow the smallest details and nuances to tell. The tonality is based firmly on C, at the lower and upper octave, and, once begun, the singer should have no difficulty in keeping pitches safely anchored, since this ‘tonic’ is frequently and reassuringly revisited throughout the piece. Medium range encourages a warm, resonant quality, but the singer must not allow vibrato to become too rich, obscuring detail or word clarity. Changes of time signature help to give a feeling of flexibility, but, as always in unaccompanied pieces, it is very important to keep a sense of pulse and forward impetus, especially through the rests which pepper the opening paragraphs.
JONATHAN COLE (b. 1970)Sorful Ter (1997, revised 2001)
Authors: Manning Jane
Published: February 2021

This chapter focuses on British composer Jonathan Cole’s Sorful Ter (1997, revised 2001). This pair of settings of complementary medieval poems displays Cole’s strong compositional persona and sensitivity to atmosphere. The two songs are extremely moving, unified by the fact that the same character, the Virgin Mary, is singing. In the first (‘The Virgin’s Song’), she bemoans in a lullaby the poverty-stricken fate of her baby son, and in the second (‘Lovely Tear of Lovely Eye’), she agonizes over his death. The musical treatment, however, is markedly different. The first song is relatively straightforward and intimate in feeling, but the second is elaborate in the extreme—teeming with decorations, trills, grace notes, and intricate rhythms. Both performers are given a highly satisfying task. The pianist will be kept fully exercised, with a wealth of bravura passages and piercing rhythmic patterns. Despite the atonality of the idiom, the composer frequently returns to an anchoring base note, even amongst the most florid vocal lines, and this will help the singer’s orientation.
JOEL FEIGIN (b. 1951)Two Songs from ‘Twelfth Night’ (2013)
Authors: Manning Jane
Published: February 2021

This chapter focuses on Joel Feigin’s Two Songs from ‘Twelfth Night’ (2013). This is but a small and relatively simple example of Feigin’s work, which embraces a great variety of styles and genres, and exhibits unfailingly high standards of professionalism and versatility. These settings of two well-loved Shakespeare texts have been extracted from his two-act opera, Twelfth Night. They make a pleasing concert item, suited to a light baritone who is happy sustaining cantabile lines which are sometimes exposed at key moments. The writing is, in general, lyrical and smooth, and proceeds in a straightforward, often identifiably tonal idiom, with just a few corners where pitches can deceive, especially in enharmonic relationships. Both settings are basically minuets—the first lithe and graceful, the second with a more sombre tread to its three-in-a-bar. Both also have slow codas which put the singer’s tonal steadiness under the microscope. Meanwhile, the piano parts veer between a lean sprightliness and warmer, shifting chordal chromaticism, supporting the voice with sensitivity at all times.
LORI LAITMAN (b. 1955)Men with Small Heads (2000)
Authors: Manning Jane
Published: February 2021

This chapter studies Lori Laitman’s Men with Small Heads (2000). From a large and tempting selection of song cycles, this one is especially to be prized, since the counter-tenor repertoire is in need of a boost. The piece, though, lies just as well for mezzo or baritone. It fizzes with confidence and verve from start to finish, with words always audible, as long as the singer has the requisite verbal panache and slickness. The texts are a delight too—their bracing ironies aptly captured throughout. The composer has given careful thought to phrasing, and her markings throughout demonstrate her innate understanding of the voice. The words do, of course, suit an American accent, and this should be borne in mind. The musical idiom is neatly poised on the edge of tonality, identifiably ‘American’ yet entirely personal and cohesive, with an inbuilt rhythmic flexibility tailored to the flow of the texts. The piano writing also has flair and vitality and is clear-textured enough for the voice to come through.
MICHAEL TORKE (b. 1961)House and Home (2012)
Authors: Manning Jane
Published: February 2021

This chapter assesses Michael Torke’s House and Home (2012). This sparkling tour de force is guaranteed to brighten up any recital. Torke is a master of post-minimalism and his work is consistently enjoyable, full of flair and verve. The entertainingly emphatic text is taken from Shakespeare’s Henry IV, Part II: Mistress Quickly’s angry diatribe at Falstaff’s uncontrollable appetite. Performers will be aware that passages of repetitive machine-like rhythms, especially in a tonal idiom, have great audience appeal, but can be much harder to bring off than more expansive, obviously virtuosic music. There is a real danger of going off the rails in the cumulative excitement generated. Assiduous preparation is essential in order to produce the desired result of unflustered elan. Moreover, placing consonants in exact rhythm warrants careful attention, and breathing must be strictly in tempo—the slightest hesitancy will be noticeable.
“Walked Out on the Platinum!,” or New York, New York
Authors: Nadel Ira
Published: February 2021

This chapter looks at Roth’s discontent with the promotion and distribution of his first and second novels, his legal separation from the intractable Maggie, his decision to shift editors at Random House from Joe Fox to Jason Epstein after the poor reception of When She Was Good, and his constant search for success. Also covered are the growing importance to Roth of psychoanalysis and his special relationship with his therapist, who publicly discussed Roth in a 1967 article without the writer’s permission. Roth’s reaction was scathing. A new style emerged, seen in a series of short stories and excerpts from his new work with titles like “Whacking Off.” Alimony and the absence of financial security were burdens. Roth began a new relationship, with the socialite Ann Mudge, the antithesis of Maggie: refined, educated, poised, and supportive.
Portnoy: “Let It Rip”
Authors: Nadel Ira
Published: February 2021

The publication of Portnoy’s Complaint and how it overturned Roth’s life is the focus of Chapter Five. His response to the overwhelming publicity, attention, and money led to his retreat from city life, first to Woodstock, New York, and than Cornwall Bridge, Connecticut where he bought an 18th-century home. He was suddenly a celebrity but wanted none of it. Yet the attention prevented him from getting on with new work as he turned to satire, notably Our Gang, The Breast and The Great American Novel , dealing with Nixon, Kafka and baseball. Nevertheless, Portnoy had a serious impact on American writing and behavior discussed in the chapter.
Jewish Wheaties
Authors: Nadel Ira
Published: February 2021

Roth travels with Barbara Sproul to Asia, while maintaining his opposition to the Vietnam War; his writing turns to satire in a general effort to undermine seriousness in politics and literature Baseball, long a love of Roth’s, emerges in his lengthy burlesque novel, The Great American Novel followed by his semi-autobiographical My Life as a Man (1974), a rebuke to his first wife, Maggie. In the midst of his writing, a bitter legal encounter with Norman Mailer involving the young writer Alan Lelchuk occurs, at the same time he develops a friendship with the important Jewish writer Cynthia Ozick, who admired Roth’s rewrite of Kafka, The Breast. But he also experiences sustained criticism from Irving Howe which he never forgot. Roth unexpectedly changes publishers leaving Random House for Holt with a new editor and soon-to-be friend, Aaron Asher.
Sir Philip John Randle. 16 July 1926—26 September 2006
Authors: Ashcroft S. J. H. , Denton R. M.
Published: February 2021

Sir Philip Randle, who died aged 80 on 26 September 2006 after a brief illness, was one of the world's foremost researchers into mammalian metabolism. In a career spanning some five decades, he provided a series of brilliant insights into the fundamental mechanisms that determine the selection of metabolic fuels by muscle and other tissues. Many of his findings were concerned with the role of insulin, including the control of its secretion from the β-cells in the pancreatic islets of Langerhans, and with the regulation of glucose oxidation through changes in the activity of pyruvate dehydrogenase. The ideas generated by his investigations laid the foundations for countless subsequent studies and have had a direct bearing on the understanding of diabetes. His lifelong enthusiasm for good research has had a great influence on all who worked with him.
The Wild Garden: landscaping southern California in the early twentieth century
Authors: Guerrini Anita
Published: February 2021

The California Wild Garden opened in Exposition Park in Los Angeles in 1916. Planned by the English horticulturist Theodore Payne (1872–1963), it featured hundreds of Californian plants. Payne claimed scientific expertise as well as practical knowledge. In the next decade, he was also instrumental in the foundation of botanic gardens in Santa Barbara and Santa Ana, which focused on native plants and had both scientific and aesthetic aims. Earlier in his career, he had championed the distribution of millions of non-native eucalyptus trees throughout the state. This essay examines Payne's multiple roles, and the liminal space occupied by horticulturists between gardening and science in progressive-era California.
Genetic regulation and heritability of miRNA and mRNA expression link to phosphorus utilization and gut microbiome
Authors: Ponsuksili Siriluck , Oster Michael , Reyer Henry , Hadlich Frieder , Trakooljul Nares , Rodehutscord Markus , Camarinha-Silva Amélia , Bennewitz Jörn , Wimmers Klaus
Published: February 2021

Improved utilization of phytates and mineral phosphorus (P) in monogastric animals contributes significantly to preserving the finite resource of mineral P and mitigating environmental pollution. In order to identify pathways and to prioritize candidate genes related to P utilization (PU), the genomic heritability of 77 and 80 trait-dependent expressed miRNAs and mRNAs in 482 Japanese quail were estimated and eQTL (expression quantitative trait loci) were detected. In total, 104 miR-eQTL (microRNA expression quantitative traits loci) were associated with SNP markers (false discovery rate less than 10%) including 41 eQTL of eight miRNAs. Similarly, 944 mRNA-eQTL were identified at the 5% False discovery rate threshold, with 573 being cis-eQTL of 36 mRNAs. High heritabilities of miRNA and mRNA expression coincide with highly significant eQTL. Integration of phenotypic data with transcriptome and microbiome data of the same animals revealed genetic regulated mRNA and miRNA transcripts (SMAD3, CAV1, ENNPP6, ATP2B4, miR-148a-3p, miR-146b-5p, miR-16-5p, miR-194, miR-215-5p, miR-199-3p, miR-1388a-3p) and microbes (

Candidatus
Arthromitus
, Enterococcus

) that are associated with PU. The results reveal novel insights into the role of mRNAs and miRNAs in host gut tissue functions, which are involved in PU and other related traits, in terms of the genetic regulation and inheritance of their expression and in association with microbiota components.
To form and function: on the role of basement membrane mechanics in tissue development, homeostasis and disease
Authors: Khalilgharibi Nargess , Mao Yanlan
Published: February 2021

The basement membrane (BM) is a special type of extracellular matrix that lines the basal side of epithelial and endothelial tissues. Functionally, the BM is important for providing physical and biochemical cues to the overlying cells, sculpting the tissue into its correct size and shape. In this review, we focus on recent studies that have unveiled the complex mechanical properties of the BM. We discuss how these properties can change during development, homeostasis and disease via different molecular mechanisms, and the subsequent impact on tissue form and function in a variety of organisms. We also explore how better characterization of BM mechanics can contribute to disease diagnosis and treatment, as well as development of better
in silico
and
in vitro
models that not only impact the fields of tissue engineering and regenerative medicine, but can also reduce the use of animals in research.
Regulation of ecdysone production in
Drosophila
by neuropeptides and peptide hormones
Authors: Kannangara Jade R. , Mirth Christen K. , Warr Coral G.
Published: February 2021

In both mammals and insects, steroid hormones play a major role in directing the animal's progression through developmental stages. To maximize fitness outcomes, steroid hormone production is regulated by the environmental conditions experienced by the animal. In insects, the steroid hormone ecdysone mediates transitions between developmental stages and is regulated in response to environmental factors such as nutrition. These environmental signals are communicated to the ecdysone-producing gland via the action of neuropeptide and peptide hormone signalling pathways. While some of these pathways have been well characterized, there is evidence to suggest more signalling pathways than has previously been thought function to control ecdysone production, potentially in response to a greater range of environmental conditions. Here, we review the neuropeptide and peptide hormone signalling pathways known to regulate the production of ecdysone in the model genetic insect
Drosophila melanogaster
, as well as what is known regarding the environmental signals that trigger these pathways. Areas for future research are highlighted that can further contribute to our overall understanding of the complex orchestration of environmental, physiological and developmental cues that together produce a functioning adult organism.
A new species ofProegerniafrom the Namba Formation in South Australia and the early evolution and environment of Australian egerniine skinks
Authors: Thorn K. M. , Hutchinson M. N. , Lee M. S. Y. , Brown N. J. , Camens A. B. , Worthy T. H.
Published: February 2021

The diverse living Australian lizard fauna contrasts greatly with their limited Oligo-Miocene fossil record. New Oligo-Miocene fossil vertebrates from the Namba Formation (south of Lake Frome, South Australia) were uncovered from multiple expeditions from 2007 to 2018. Abundant disarticulated material of small vertebrates was concentrated in shallow lenses along the palaeolake edges, now exposed on the western of Lake Pinpa also known from Billeroo Creek 2 km northeast. The fossiliferous lens within the Namba Formation hosting the abundant aquatic (such as fish, platypusObdurodonand waterfowl) and diverse terrestrial (such as possums, dasyuromorphs and scincids) vertebrates and is hereafter recognized as the Fish Lens. The stratigraphic provenance of these deposits in relation to prior finds in the area is also established. A new egerniine scincid taxonProegernia mikebullisp. nov. described herein, is based on a near-complete reconstructed mandible, maxilla, premaxilla and pterygoid. Postcranial scincid elements were also recovered with this material, but could not yet be confidently associated withP. mikebulli. This new taxon is recovered as the sister species toP. palankarinnensis, in a tip-dated total-evidence phylogenetic analysis, where both are recovered as stem Australian egerniines. These taxa also help pinpoint the timing of the arrival of scincids to Australia, with egerniines the first radiation to reach the continent.
Addendum 2020 to ‘Measurement of the Earth’s rotation: 720 BC to AD 2015’
Authors: Morrison L. V. , Stephenson F. R. , Hohenkerk C. Y. , Zawilski M.
Published: February 2021

Historical reports of solar eclipses are added to our previous dataset (Stephenson
et al.
2016
Proc. R. Soc. A
472
, 20160404 (
doi:10.1098/rspa.2016.0404
)) in order to refine our determination of centennial and longer-term changes since 720 BC in the rate of rotation of the Earth. The revised observed deceleration is −4.59 ± 0.08 × 10
−22
 rad s
−2
. By comparison the predicted tidal deceleration based on the conservation of angular momentum in the Sun–Earth–Moon system is −6.39 ± 0.03 × 10
−22
 rad s
−2
. These signify a mean accelerative component of +1.8 ± 0.1 × 10
−22
 rad s
−2
. There is also evidence of an oscillatory variation in the rate with a period of about 14 centuries.
Rogue waves of ultra-high peak amplitude: a mechanism for reaching up to a thousand times the background level
Authors: Sun Wen-Rong , Liu Lei , Kevrekidis P. G.
Published: February 2021

We unveil a mechanism enabling a fundamental rogue wave, expressed by a rational function of fourth degree, to reach a peak amplitude as high as a thousand times the background level in a system of coupled nonlinear Schrödinger equations involving both incoherent and coherent coupling terms with suitable coefficients. We obtain the exact explicit vector rational solutions using a Darboux-dressing transformation. We show that
both
components of such coupled equations can reach extremely high amplitudes. The mechanism is confirmed in direct numerical simulations and its robustness is confirmed upon noisy perturbations. Additionally, we showcase the fact that extremely high peak-amplitude vector fundamental rogue waves (of about 80 times the background level) can be excited even within a
chaotic background field
.
Enhanced problem-solving ability as an adaptation to urban environments in house mice
Authors: Vrbanec Lara , Matijević Vanja , Guenther Anja
Published: February 2021

Humans have a large impact on the distribution and abundance of animal species worldwide. The ecological effects of human-altered environments are being increasingly recognized and understood, but their effects on evolution are largely unknown. Enhanced cognitive abilities and the ability to innovate have been suggested as crucial traits for thriving in human-altered habitats. We tested if house mice (
Mus musculus
) subspecies have evolved enhanced innovative problem-solving abilities throughout their commensal lives with humans. The time that subspecies lived commensally with humans ranges between approximately 3000 years to more than 11 000 years, thus providing an excellent example of human–animal coexistence. In addition, we tested whether differences in problem-solving were mediated by differences in object and place exploration, motivation, persistence or inhibitory control. We found that populations of subspecies living commensally the longest excelled in problem-solving across seven food-extraction tasks over subspecies living commensally short or intermediate times. These differences were not mediated by exploration, motivation, persistence or inhibitory control suggesting that subspecies have evolved better cognitive abilities when living commensally in urban environments. This suggests that the ability to problem-solve may be an important trait promoting prosperity in human-altered environments.
Intraspecific niche partition without speciation: individual level web polymorphism within a single island spider population
Authors: Cotoras Darko D. , Suenaga Miyuki , Mikheyev Alexander S.
Published: February 2021

Early in the process of adaptive radiation, allopatric disruption of gene flow followed by ecological specialization is key for speciation; but, do adaptive radiations occur on small islands without internal geographical barriers? Island populations sometimes harbour polymorphism in ecological specializations, but its significance remains unclear. On one hand, morphs may correspond to ‘cryptic’ species. Alternatively, they could result from population, developmental or behavioural plasticity. The spiderWendilgarda galapagensis(Araneae, Theridiosomatidae) is endemic to the small Isla del Coco and unique in spinning three different web types, each corresponding to a different microhabitat. We tested whether this variation is associated with ‘cryptic’ species or intraspecific behavioural plasticity. Despite analysing 36 803 loci across 142 individuals, we found no relationship between web type and population structure, which was only weakly geographically differentiated. The same pattern holds when looking within a sampling site or considering onlyFstoutliers. In line with genetic data, translocation experiments showed that web architecture is plastic within an individual. However, not all transitions between web types are equally probable, indicating the existence of individual preferences. Our data supports the idea that diversification on small islands might occur mainly at the behavioural level producing an intraspecific niche partition without speciation.
The role of dectin-1 signaling in altering tumor immune microenvironment in the context of aging
Authors: Bhaskaran Natarajan , Jayaraman Sangeetha , Quigley Cheriese , Mamileti Prerna , Ghannoum Mahmoud , Weinberg Aaron , Thuener Jason , Pan Quintin , Pandiyan Pushpa
Published: February 2021

An increased accumulation of immune-dysfunction-associated CD4+Foxp3+regulatory T cells (Tregs) is observed in aging oral mucosa during infection. Here we studied the function of Tregsduring oral cancer development in aging mucosa. First, we found heightened proportions of Tregsand myeloid-derived suppressor cells (MDSC) accumulating in mouse and human oral squamous cell carcinoma (OSCC) tissues. Using the mouse 4-Nitroquinoline 1-oxide(4-NQO) oral carcinogenesis model, we found that tongues of aged mice displayed increased propensity for epithelial cell dysplasia, hyperplasia, and accelerated OSCC development, which coincided with significantly increased abundance of IL-1β, Tregs, and MDSC in tongues. Partial depletion of Tregsreduced tumor burden. Moreover, fungal abundance and dectin-1 signaling were elevated in aged mice suggesting a potential role for dectin-1 in modulating immune environment and tumor development. Confirming this tenet, dectin-1 deficient mice showed diminished IL-1β, reduced infiltration of Tregsand MDSC in the tongues, as well as slower progression and reduced severity of tumor burden. Taken together, these data identify an important role of dectin-1 signaling in establishing the intra-tumoral immunosuppressive milieu and promoting OSCC tumorigenesis in the context of aging.
Metagenomes from the Loxahatchee wildlife refuge in the Florida Everglades
Authors: Alvarez David A , Cadavid Nikolya A , Childs Cale A , Cupelli Matthew F , De Leao Victoria A , Diaz Alyssa M , Eldridge Sophie A , Elhabashy Yasmin B , Fleming Allison E , Fox Nathan A , Franco Marianna , Gaspari James C , Gerstin Isabella M , Gibson Kimberlee A , Huott Alyssa L , Johnson Alex O , Majhess Ellie G , Mantilla Gabriela , Perez Gabriella S , Prieto Juliet J , Reutter Bridget C , Rivera Elena I , Rootes Thomas R , Sellers Jade , Streibig Allison M , Wilkinson Joseph S , Zayas-Bazan Siona , Bhadha Jehangir H. , Clum Alicia , Daum Christopher , Glavina del Rio Tijana , Lail Kathleen , Roux Simon , Eloe-Fadrosh Emiley A. , Benskin Jonathan B.
Published: February 2021

The Florida Everglades ecosystem represents a significant wetlands area and serves as a terrestrial carbon reservoir mediated in large part by microorganisms. Shotgun metagenome sequencing provides a snapshot of microbial diversity and the frequency of metabolic and functional gene content. Here, we present an analysis of 20 sediment samples collected from the Arthur R. Marshall Loxahatchee National Wildlife Refuge to characterize the taxonomic and functional potential of the microbial and viral communities, and reconstructed metagenome-assembled genomes. A total of 122 medium-quality and 6 high-quality MAGs are reported, three of which likely represent a novel species within the class Dehalococcoidia.

The most abundant phyla of bacteria and archaea were Proteobacteria and Euryarchaeota, respectively. Caudovirales was the most abundant viral order. Significant differences in taxonomic composition and diversity were observed among collection sites. Additionally, water samples were analyzed for pH, total nitrogen, total organic carbon, elements (P, K, Mg, Fe, Mn, Pb, Ca, S), chloride, electric conductivity, orthophosphate, nitrate, and ammonia, while the sediment samples were analyzed for carbon, nitrogen, and pH. Differences in measured aquatic and sediment analytes revealed significant correlations with numerous phyla. Significant correlations were observed between estimated gene frequencies of both aquatic and sediment analytes, most notably between kup/kdpB and dsrA/cysC with potassium and sulfur, respectively, as well as phoD/phnX and cysC with pH. Together, these data provide an important view into the functional and metabolic potential encoded within the sediment microbial communities in the Florida Everglades.
501Y.V2 and 501Y.V3 variants of SARS-CoV-2 lose binding to Bamlanivimabin vitro
Authors: Liu Haolin , Wei Pengcheng , Zhang Qianqian , Chen Zhongzhou , Aviszus Katja , Downing Walter , Peterson Shelley , Reynoso Lyndon , Downey Gregory P. , Frankel Stephen K. , Kappler John , Marrack Philippa , Zhang Gongyi
Published: February 2021

We generated several versions of the receptor binding domain (RBD) of the Spike protein with mutations existing within newly emerging variants from South Africa and Brazil. We found that the mutant RBD with K417N, E484K, and N501Y exchanges has higher binding affinity to the human receptor compared to the wildtype RBD. This mutated version of RBD also completely abolishes the binding to a therapeutic antibody, Bamlanivimab,in vitro.
Transposable Elements Shape Stemness in Normal and Leukemic Hematopoiesis
Authors: Grillo Giacomo , Nadorp Bettina , Qamra Aditi , Mitchell Amanda , Arlidge Christopher , Nand Ankita , Takayama Naoya , Murison Alex , Tonekaboni Seyed Ali Madani , Arruda Andrea , Wang Jean C. Y. , Minden Mark D. , Deniz Özgen , Boutzen Héléna , Dick John E. , Lupien Mathieu
Published: February 2021

Despite most acute myeloid leukemia (AML) patients achieving complete remission after induction chemotherapy, two-thirds will relapse with fatal disease within five years. AML is organized as a cellular hierarchy sustained by leukemia stem cells (LSC) at the apex, with LSC properties directly linked to tumor progression, therapy failure, and disease relapse1–5. Despite the central role of LSC in poor patient outcomes, little is known about the genetic determinants driving their stemness properties. As LSCs share many functional and molecular properties with normal hematopoietic stem cells (HSC)6, we investigated accessible chromatin unique across normal hematopoietic and cancer cell states and identified transposable elements (TEs) as genetic determinants of both primitive populations in comparison with their downstream mature progeny. A clinically-relevant TE chromatin accessibility-based LSCTE121 signature was developed that enabled patient classification based on survival outcomes. Through functional assays, primitive cell specific-TE subfamilies were found to serve as docking sites for stem cell-associated regulators of genome topology or lineage-specific transcription factors, including LYL1 in LSCs. Finally, using chromatin editing tools, we establish that chromatin accessibility at LTR12C elements in LSCs are necessary to maintain stemness properties. Our work identifies TEs as genetic drivers of primitive versus mature cell states, where distinct TE subfamilies account for stemness properties in normal versus leukemic hematopoietic stem cells.
Slow chromatin dynamics enhances promoter accessibility to transcriptional condensates
Authors: Yamamoto Tetsuya , Sakaue Takahiro , Schiessel Helmut
Published: February 2021

Enhancers are DNA sequences at a long genomic distance from target genes. Recent experiments suggest that enhancers are anchored to the surfaces of condensates of transcription machinery and that the loop extrusion process enhances the transcription level of their target genes. Here we theoretically study the polymer dynamics driven by the loop extrusion of the linker DNA between an enhancer and the promoter of its target gene to calculate the contact probability of the promoter to the transcription machinery in the condensate. Our theory predicts that when the loop extrusion process is active, the contact probability increases with increasing linker DNA length. This finding reflects the fact that the relaxation time, with which the promoter stays in proximity to the surface of the transcriptional condensate, increases as the length of the linker DNA increases. This contrasts the equilibrium case for which the contact probability between the promoter and the transcription machineries is smaller for longer linker DNA lengths.
MultiMAP: Dimensionality Reduction and Integration of Multimodal Data
Authors: Jain Mika Sarkin , Polanski Krzysztof , Conde Cecilia Dominguez , Chen Xi , Park Jongeun , Mamanova Lira , Knights Andrew , Botting Rachel A. , Stephenson Emily , Haniffa Muzlifah , Lamacraft Austen , Efremova Mirjana , Teichmann Sarah A.
Published: February 2021

Multimodal data is rapidly growing in many fields of science and engineering, including single-cell biology. We introduce MultiMAP, an approach for dimensionality reduction and integration of multiple datasets. MultiMAP recovers a single manifold on which all of the data resides and then projects the data into a single low-dimensional space so as to preserve the structure of the manifold. It is based on a framework of Riemannian geometry and algebraic topology, and generalizes the popular UMAP algorithm1to the multimodal setting. MultiMAP can be used for visualization of multimodal data, and as an integration approach that enables joint analyses. MultiMAP has several advantages over existing integration strategies for single-cell data, including that MultiMAP can integrate any number of datasets, leverages features that are not present in all datasets (i.e. datasets can be of different dimensionalities), is not restricted to a linear mapping, can control the influence of each dataset on the embedding, and is extremely scalable to large datasets. We apply MultiMAP to the integration of a variety of single-cell transcriptomics, chromatin accessibility, methylation, and spatial data, and show that it outperforms current approaches in preservation of high-dimensional structure, alignment of datasets, visual separation of clusters, transfer learning, and runtime. On a newly generated single-cell Assay for Transposase-Accessible Chromatin using sequencing (scATAC-seq) and single-cell RNA-seq (scRNA-seq) dataset of the human thymus, we use MultiMAP to integrate cells along a temporal trajectory. This enables the quantitative comparison of transcription factor expression and binding site accessibility over the course of T cell differentiation, revealing patterns of transcription factor kinetics.
Ketamine disrupts gaze patterns during face viewing in the common marmoset
Authors: Selvanayagam Janahan , Johnston Kevin D. , Wong Raymond K. , Schaeffer David J. , Everling Stefan
Published: February 2021

Faces are stimuli of critical importance for primates. The common marmoset (Callithrix jacchus) is a promising model for investigations of face processing, as this species possesses oculomotor and face processing networks resembling those of macaques and humans. Face processing is often disrupted in neuropsychiatric conditions such as schizophrenia (SZ) and thus it is important to recapitulate underlying circuitry dysfunction preclinically. The N-Methyl-D-aspartate (NMDA) non-competitive antagonist ketamine has been used extensively to model the cognitive symptoms of SZ. Here, we investigated the effects of a subanesthetic dose of ketamine on oculomotor behaviour in marmosets during face viewing. Four marmosets received systemic ketamine or saline injections while viewing phase-scrambled or intact videos of conspecifics’ faces. To evaluate effects of ketamine on scan paths during face viewing, we identified regions of interest in each face video, and classified locations of saccade onsets and landing positions within these areas. A preference for the snout over eye regions was observed following ketamine administration. In addition, regions in which saccades landed could be significantly predicted by saccade onset region in the saline but not the ketamine condition. No significant drug effects were observed for phase-scrambled videos. Effects on saccade control were limited to a reduction in saccade amplitudes during viewing of scrambled videos. Thus, ketamine induced a significant disruption of scan paths during viewing of conspecific faces but limited effects on saccade motor control. These findings support the use of ketamine in marmosets for investigating changes in neural circuits underlying social cognition in neuropsychiatric disorders.
Cholecystokinin 1 Receptor (Cck1R) Normalizes mTORC1 signaling and is Protective to Purkinje cells of SCA Mice
Authors: Wozniak Emily A.L. , Chen Zhao , Paul Sharan , Yang Praseuth , Figueroa Karla P. , Friedrich Jill , Tschumperlin Tyler , Berken Michael , Ingram Melissa , Henzler Christine , Pulst Stefan M. , Orr Harry T.
Published: February 2021

Spinocerebellar Ataxias (SCAs) are a group of genetic diseases characterized by progressive ataxia and neurodegeneration, often in cerebellar Purkinje neurons. A SCA1 mouse model,Pcp2-ATXN1[30Q]D776, has severe ataxia in absence of progressive Purkinje neuron degeneration and death. Previous RNA-seq analyses identified cerebellar up-regulation of the peptide hormone Cholecystokinin (Cck) inPcp2-ATXN1[30Q]D776mice. Importantly, absence of Cck1 receptor (Cck1R) inPcp2-ATXN1[30Q]D776mice confers a progressive disease with Purkinje neuron death. A Cck1R agonist, A71623 administered toPcp2-ATXN1[30Q]D776;Cck-/-andPcp2-AXTN1[82Q]mice dampened Purkinje neuron pathology and associated deficits in motor performance. In addition, A71623 administration improved motor performance ofPcp2-ATXN2[127Q]SCA2 mice. Moreover, the Cck1R agonist A71623 corrected mTORC1 signaling and improved expression of calbindin in cerebella ofAXTN1[82Q]andATXN2[127Q]mice. These results indicate that manipulation of the Cck-Cck1R pathway is a potential therapeutic target for treatment of diseases involving Purkinje neuron degeneration.
Towards a further step in understanding business excellence models: a comparative approach
Authors: Alanazi Mohammed Hamdan
Published: February 2021

Purpose

A comparative analysis of the validity of business excellence models (BEMs) has rarely been empirically pursued. In addition to their similarities, BEMs exhibit differences in terms of their criteria, relations and emphasis, and some researchers have claimed that it is because these models tend to represent underlying cultural, economic, or social dynamics, as well as global best practices. Based on three such BEMs (the Malcolm Baldrige National Quality Award (MBNQA) model, the European Foundation for Quality Management (EFQM) model and the King Abdul Aziz Quality Award (KAQA) model), this paper introduces a four-phase study to analyse these models comparatively.

Design/methodology/approach

This paper: (1) conceptually delineates the distinctive natures of and differences between the three models; (2) develops a comprehensive measurement model based on the content of these models; (3) reviews the relevant literature on BEMs; (4) discusses the motivation behind this comparative approach and (5) introduces a four-phase study to comparatively analyse these models.

Findings

A comprehensive measurement model and three structural models are developed, but empirical tests have not been performed. This developed approach is introduced here as a first step in the advancement of our understanding of BEMs and their underlying theory.

Originality/value

The range of variability and complexity of BEMs—i.e. a holistic and comparative empirical view of BEMs—have not so far been fully considered, and findings in this domain tend to be inclusive, while some of the underlying relations of these models have not been investigated. This paper contributes to filling these research gaps.
The social ecology of sexual victimization against transgender women who are incarcerated: A call for (more) research on modalities of housing and prison violence
Authors: Jenness Valerie
Published: February 2021

President Biden has called for reform of the criminal justice system to ensure fair treatment of people who are transgender who come into contact with the criminal justice system. He has done so in a context in which criminologists, public health researchers, and others, including journalists and advocates, have produced a growing body of research that documents the over criminalization and differential incarceration of people who are transgender as well as the high rates of victimization of transgender women who are incarcerated. Accordingly, this article describes a growing literature on the sexual victimization experienced by transgender women who are incarcerated; focuses analytic attention on the housing contexts in which this kind of discriminatory gendered violence emerges and takes shape; points to some emergent policy responses related to these concerns; and calls for original research that, if conducted, could advance the criminological literature in meaningful ways and set the stage for evidence‐based prison policy and practice related to what is now predictably high rates of violence against transgender women who are incarcerated.
A survey of anxiety and burnout in the radiology workforce of a tertiary hospital during the COVID‐19 pandemic
Authors: Huang Hian Liang , Chen Robert Chun , Teo Irene , Chaudhry Isha , Heng Ai Ling , Zhuang Kun Da , Tan Hiang Khoon , Tan Bien Soo
Published: February 2021

Introduction

We aimed to study anxiety and burnout among Division of Radiological Sciences (RADSC) staff during the COVID‐19 pandemic and identify potential risk and protective factors. These outcomes were compared with non‐RADSC staff.

Methods

A cross‐sectional online study was conducted between 12 March and 20 July 2020 in the largest public tertiary hospital receiving COVID‐19 cases. Burnout and anxiety were assessed with the Physician Work‐Life Scale and the Generalized Anxiety Disorder‐7 Scale, respectively. Workplace factors were examined as potential risk and protective factors using multivariable ordinary least squares regression analyses, adjusting for pertinent demographic characteristics.

Results

RADSC staff (n = 180) and non‐RADSC staff (n = 1458) demonstrated moderate‐to‐severe anxiety rates of 6.7 and 13.2 % and burnout rates of 17.8 and 23.9 %, respectively. RADSC staff reported significantly lower anxiety (mean ± SD: 4.0 ± 3.7 vs 4.9 ± 4.5; P‐value < 0.05), burnout (mean ± SD: 1.9 ± 0.7 vs 2.1 ± 0.8; P‐value < 0.01), increased teamwork (82.2% vs 74.1%; P‐value < 0.05) and fewer night shifts (36.7% vs 41.1%; P‐value < 0.01). Among RADSC staff, higher job dedication was associated with lower anxiety (b (95% CI) = −0.28 (−0.45, −0.11)) and burnout (b (95% CI) = −0.07 (−0.11,‐0.04)), while longer than usual working hours was associated with increased anxiety (b (95% CI) = 1.42 (0.36, 2.45)) and burnout (b (95% CI) = 0.28 (0.09, 0.48)).

Conclusions

A proportion of RADSC staff reported significant burnout and anxiety, although less compared to the larger hospital cohort. Measures to prevent longer than usual work hours and increase feelings of enthusiasm and pride in one’s job may further reduce the prevalence of anxiety problems and burnout in radiology departments.
Second‐line therapy with first‐ or second‐generation tyrosine kinase inhibitors in EGFR‐mutated non‐small cell lung cancer patients with T790M‐negative or unidentified mutation
Authors: Nishimura Tadashi , Okano Tomohito , Naito Masahiro , Iwanaka Soichi , Ohiwa Ayaka , Sakakura Yasumasa , Yasuma Taro , Fujimoto Hajime , D'Alessandro‐Gabazza Corina N. , Oomoto Yasuhiro , Kobayashi Tetsu , Gabazza Esteban C. , Ibata Hidenori
Published: February 2021

Background

T790M mutation causes resistance to tyrosine kinase inhibitors (TKIs) in approximately 49% of patients with epidermal growth receptor‐mutant non‐small cell lung cancer (NSCLC). The cause of resistance in the remaining half of the cases is a minor mutation or unknown. Here, we conducted a retrospective study of epidermal growth receptor‐mutant NSCLC patients with T790M‐negative or an unidentified mutation to appraise the therapeutic response to first‐ or second‐generation tyrosine kinase inhibitors as a second‐line treatment.

Methods

The study included 39 patients treated in our institution from April 2012 through March 2020 with second‐line tyrosine kinase inhibitors or chemotherapy after completing a first‐line therapy with tyrosine kinase inhibitors.

Results

The patients were allocated to two groups: chemotherapy (n = 28) and a tyrosine kinase inhibitor (n = 11) groups. The median progression‐free survival (PFS) was 5.4 months in the chemotherapy group and 3.4 months in the tyrosine kinase inhibitor group (p‐value = 0.36), while the median overall survival (OS) was 16.1 months in the chemotherapy group and 12.8 months in the tyrosine kinase inhibitor group (p‐ value = 0.20). This study showed no significant difference in PFS and OS between the chemotherapy and tyrosine kinase inhibitor groups.

Conclusions

These observations suggest that first‐ and second‐generation tyrosine kinase inhibitors are not recommended for second‐line treatment in epidermal growth factor receptor‐mutated NSCLC patients with T790M‐negative mutation who have received tyrosine kinase inhibitors as first‐line treatment.
Impact of reirradiation, chemotherapy, and immunotherapy on survival of patients with recurrent lung cancer: A single‐center retrospective analysis
Authors: Grambozov Brane , Wass Romana , Stana Markus , Gerum Sabine , Karner Josef , Fastner Gerd , Studnicka Michael , Sedlmayer Felix , Zehentmayr Franz
Published: February 2021

Background

Given the limited curative treatment options for recurrent lung cancer patients, the aim of our retrospective study was to investigate whether these patients would benefit in terms of overall survival (OS) by adding immunotherapy to high‐dose reirradiation.

Materials and methods

Between 2013 and 2019, 47 consecutive patients with in‐field tumor recurrence underwent high‐dose thoracic reirradiation at our institute. Twenty patients (43%) received high‐dose reirradiation only, while 27/47 (57%) additionally had systemic therapy (immunotherapy and/or chemotherapy). With the exception of one patent, the interval between first and second radiation was at least 9 months. All patients had an Eastern cooperative oncology group ≤2. The diagnostic work‐up included a mandatory fluorodeoxyglucose‐positron emission tomography‐computed tomography scan and histological verification. The primary endpoint was OS after completion of the second course of irradiation.

Results

In the whole cohort of 47 patients, the median overall survival (mOS) after reirradiation was 18.9 months (95% confidence interval [CI] 16.5–21.3 months), while in the subgroup of 27 patients who received additional systemic treatment after reirradiation, mOS amounted to 21.8 months (95% CI 17.8–25.8 months). Within this group the comparison between reirradiation combined with either immunotherapy (n = 21) or chemotherapy (n = 6) revealed a difference in OS, which was in favor of the first (log‐rank p value = 0.063). Three patients (11%) experienced acute side effects and one (4%) showed a late hemorrhage grade 3.

Conclusion

Patients who received immunotherapy and reirradiation lived longer than those who did not receive immunotherapy.