Elucidation of hepatitis C virus transmission and early diversification by single genome sequencing.

A precise molecular identification of transmitted hepatitis C virus (HCV) genomes could illuminate key aspects of transmission biology, immunopathogenesis and natural history. We used single genome sequencing of 2,922 half or quarter genomes from plasma viral RNA to identify transmitted/founder (T/F) viruses in 17 subjects with acute community-acquired HCV infection. Sequences from 13 of 17 acute subjects, but none of 14 chronic controls, exhibited one or more discrete low diversity viral lineages. Sequences within each lineage generally revealed a star-like phylogeny of mutations that coalesced to unambiguous T/F viral genomes. Numbers of transmitted viruses leading to productive clinical infection were estimated to range from 1 to 37 or more (median = 4). Four acutely infected subjects showed a distinctly different pattern of virus diversity that deviated from a star-like phylogeny. In these cases, empirical analysis and mathematical modeling suggested high multiplicity virus transmission from individuals who themselves were acutely infected or had experienced a virus population bottleneck due to antiviral drug therapy. These results provide new quantitative and qualitative insights into HCV transmission, revealing for the first time virus-host interactions that successful vaccines or treatment interventions will need to overcome. Our findings further suggest a novel experimental strategy for identifying full-length T/F genomes for proteome-wide analyses of HCV biology and adaptation to antiviral drug or immune pressures.

Features of programmed cell death in intact Xenopus oocytes and early embryos revealed by near-infrared fluorescence and real-time monitoring.

Factors influencing apoptosis of vertebrate eggs and early embryos have been studied in cell-free systems and in intact embryos by analyzing individual apoptotic regulators or caspase activation in static samples. A novel method for monitoring caspase activity in living Xenopus oocytes and early embryos is described here. The approach, using microinjection of a near-infrared caspase substrate that emits fluorescence only after its proteolytic cleavage by active effector caspases, has enabled the elucidation of otherwise cryptic aspects of apoptotic regulation. In particular, we show that brief caspase activity (10 min) is sufficient to cause apoptotic death in this system. We illustrate a cytochrome c dose threshold in the oocyte, which is lowered by Smac, a protein that binds thereby neutralizing the inhibitor of apoptosis proteins. We show that meiotic oocytes develop resistance to cytochrome c, and that the eventual death of oocytes arrested in meiosis is caspase-independent. Finally, data acquired through imaging caspase activity in the Xenopus embryo suggest that apoptosis in very early development is not cell-autonomous. These studies both validate this assay as a useful tool for apoptosis research and reveal subtleties in the cell death program during early development. Moreover, this method offers a potentially valuable screening modality for identifying novel apoptotic regulators.

Early social exposure in wild chimpanzees: mothers with sons are more gregarious than mothers with daughters.

In many mammals, early social experience is critical to developing species-appropriate adult behaviors. Although mother-infant interactions play an undeniably significant role in social development, other individuals in the social milieu may also influence infant outcomes. Additionally, the social skills necessary for adult success may differ between the sexes. In chimpanzees (Pan troglodytes), adult males are more gregarious than females and rely on a suite of competitive and cooperative relationships to obtain access to females. In fission-fusion species, including humans and chimpanzees, subgroup composition is labile and individuals can vary the number of individuals with whom they associate. Thus, mothers in these species have a variety of social options. In this study, we investigated whether wild chimpanzee maternal subgrouping patterns differed based on infant sex. Our results show that mothers of sons were more gregarious than mothers of daughters; differences were especially pronounced during the first 6 mo of life, when infant behavior is unlikely to influence maternal subgrouping. Furthermore, mothers with sons spent significantly more time in parties containing males during the first 6 mo. These early differences foreshadow the well-documented sex differences in adult social behavior, and maternal gregariousness may provide sons with important observational learning experiences and social exposure early in life. The presence of these patterns in chimpanzees raises questions concerning the evolutionary history of differential social exposure and its role in shaping sex-typical behavior in humans.

Pharmacogenomics in early-phase clinical development.

Pharmacogenomics (PGx) offers the promise of utilizing genetic fingerprints to predict individual responses to drugs in terms of safety, efficacy and pharmacokinetics. Early-phase clinical trial PGx applications can identify human genome variations that are meaningful to study design, selection of participants, allocation of resources and clinical research ethics. Results can inform later-phase study design and pipeline developmental decisions. Nevertheless, our review of the clinicaltrials.gov database demonstrates that PGx is rarely used by drug developers. Of the total 323 trials that included PGx as an outcome, 80% have been conducted by academic institutions after initial regulatory approval. Barriers for the application of PGx are discussed. We propose a framework for the role of PGx in early-phase drug development and recommend PGx be universally considered in study design, result interpretation and hypothesis generation for later-phase studies, but PGx results from underpowered studies should not be used by themselves to terminate drug-development programs.

Neutralizing BAFF/APRIL with atacicept prevents early DSA formation and AMR development in T cell depletion induced nonhuman primate AMR model.

Depletional strategies directed toward achieving tolerance induction in organ transplantation have been associated with an increased incidence and risk of antibody-mediated rejection (AMR) and graft injury. Our clinical data suggest correlation of increased serum B cell activating factor/survival factor (BAFF) with increased risk of antibody-mediated rejection in alemtuzumab treated patients. In the present study, we tested the ability of BAFF blockade (TACI-Ig) in a nonhuman primate AMR model to prevent alloantibody production and prolong allograft survival. Three animals received the AMR inducing regimen (CD3-IT/alefacept/tacrolimus) with TACI-Ig (atacicept), compared to five control animals treated with the AMR inducing regimen only. TACI-Ig treatment lead to decreased levels of DSA in treated animals at 2 and 4 weeks posttransplantation (p < 0.05). In addition, peripheral B cell numbers were significantly lower at 6 weeks posttransplantation. However, it provided only a marginal increase in graft survival (59 ± 22 vs. 102 ± 47 days; p = 0.11). Histological analysis revealed a substantial reduction in findings typically associated with humoral rejection with atacicept treatment. More T cell rejection findings were observed with increased graft T cell infiltration in atacicept treatment, likely secondary to the graft prolongation. We show that BAFF/APRIL blockade using concomitant TACI-Ig treatment reduced the humoral portion of rejection in our depletion-induced preclinical AMR model.

The distribution of early childhood memories.

The quantitative distribution of autobiographical memories for the first decade of life is described. The distribution, based on over 11,000 autobiographical memories from age 10 and younger from published studies, is nearly identical for males and females, for participants of different ages, and for different methods of collecting data, including using words to cue memories from anywhere in the lifespan or from just the childhood years, exhaustive listing of all early memories, and interviews.

Things learned in early adulthood are remembered best.

Evidence is reviewed that for older adults the period from 10 to 30 years of age produces recall of the most autobiographical memories, the most vivid memories, and the most important memories. It is the period from which peoples' favorite films, music, and books come and the period from which they judge the most important world events to have originated. Factual, semantic, general-knowledge, multiple-choice questions about the Academy Awards, the World Series, and current events from this period were answered more accurately by two different groups of 30 older adults tested 10 years apart. A cognitive theory based on the importance of transitions and several noncognitive theories are considered as explanations of this pervasive phenomenon.

VINTAGE MODERNISM: EARLY EXPERIMENTALIST MUSIC FOR VIOLIN IN THE UNITED STATES

The historical narrative of concert music in the early twentieth century has focused a great deal on the influence of European composers as well as the American composers who went to Europe to study. Often overlooked, however, is the influence of an entire generation of composers working in the United States during that time period. These artists experimented with polyrhythm, polytonality, dissonant counterpoint, and a whole host of other musical techniques in order to express their perceptions of a changing world. Over the years, the new techniques became associated with various movements including futurism, experimentalism and ultramodernism. Regardless of label, these composers were some of the first to introduce the new musical styles to the listening public.The recitals that make up this dissertation explore the sound world of experimentalist composers working in the United States during the early twentieth century. Serving as the foundation of these recitals are all four of the violin sonatas by Charles Ives, the “grandfather” of modernist music whose financial support helped to foster a whole generation of American composers. Also prominently featured is the music of Henry Cowell. His Suite for Violin and Piano, Mosaic Quartet (String Quartet No. 3), and Quartet Euphometric demonstrate the composer's use of cluster tones, dissonant counterpoint, polymeter, and indeterminate form. Additional works by George Antheil, Leo Ornstein, Wallingford Riegger, Dane Rudhyar, Carl Ruggles, and Ruth Crawford (Seeger) highlight other approaches taken by members of the ultra-modernist movement. Rounding out the repertoire for these recitals are works by Johanna Beyer and Conlon Nancarrow, both of whom either worked with or were influenced by Cowell in some way. All of the pieces selected date roughly from 1900 to the mid 1930's. Thus, the purpose of these recitals is not to provide a comprehensive overview of each composer's development, but rather to examine the influence and interconnections of a specific cross-section of the musical landscape.

EARLY TWENTIETH CENTURY VIOLA MUSIC FROM ENGLAND AND GERMANY: FROM POST-ROMANTICISM TO MODERNISM

In the early twentieth century, the viola began to gain status as a solo instrument with the appearance in England of the virtuosic violist Lionel Tertis. Because of a lack of music for viola at that time, such English composers as York Bowen, Arnold Bax, Ralph Vaughan Williams, Arthur Bliss and William Walton began to write viola music for Tertis. Meanwhile, in Germany, the well-known composer and virtuosic violinist and violist Paul Hindemith wrote and premiered several viola sonatas and concertos. Viola music became even more developed later with William Primrose, the legendary Scottish violist, and all the works written in the early twentieth century have remained significant in the viola literature. Although this new viola music appeared in both countries during same period, it developed along different lines in each country. Because they were under the influence of earlier periods and traditions, the English composers who associated with Tertis wrote their music in a Romantic style, with expanded harmony, various colors of sound and timbre, and lyrical melodies. Hindemith, as a composer himself, employed a more Modernist style, using atonality and angular melodies, which represented German trends at that time. I have given three recitals, of which the first two were divided between selected English music and German music. Although I originally intended to focus solely on music by Hindemith and music written for Terts, I decided that in order to give a more complete view of the national trends of those two countries, I included Rebecca Clarke's Sonata, Lachrymae by Benjamin Britten (dedicated to William Primrose), and Max Reger's Suite for Viola. Rebecca Clarke was herself a fine violist, and her sonata's Romantic style is also representative of the English trends of viola music. Lachrymae was written with a different concept and shows more modernity than had ever before occurred in England, though it still differs from the modernity of other countries. Max Reger's Suite is in a truly Romantic style, yet it is old fashioned in ways that differ not only from Wagner or Strauss, but also from English music of the period. In my last recital I wished to pay homage to Tertis, with a program consisting entirely of music written for him. For the finale, Arthur Bliss's Viola Sonata was especially chosen because it provides interesting similarities and contrasts with earlier English music in the Romantic style.

LIONEL TERTIS AND THE FLOWERING OF EARLY TWENTIETH CENTURY ENGLISH VIOLA REPERTOIRE

This performance project focused on English viola literature written in the first half of the twentieth century. During this time, numerous English composers were influenced by Lionel Tertis' unprecedented approach to the viola as a virtuosic and solo instrument. In addition to being an inspiration to composers of whom he was not in direct contact, Tertis' innovative vision for the viola led to numerous collaborations with prominent English composers of his generation. Ralph Vaughan Williams, Arnold Bax, York Bowen, Frank Bridge, Benjamin Britten, and Rebecca Clarke -his own protégé - composed some of the most important works for viola thus directly shaping the impression of the instrument as we know it today. Tertis' artistry as a performing violist was unmatched at the beginning of the twentieth century. He had a unique approach to the instrument which focused on concept of sound, tone color, concentrated listening, continuous vibrato, discreet portamento, and expressive interpretation. His convincing musical and technical ideas led him to write a treatise about how to achieve a beautiful tone. His passion for teaching and concern for the viola's posterity greatly enhanced the development of the viola. Tertis transcribed, edited, and premiered many works during his career. The music that Lionel Tertis influenced can be seen as a microcosm for a musical resurgence in England during the first half of the twentieth-century. The catalyst for this was artistic influences in the form of nationalism, folk music, romanticism, modernism, and impressionism, among others. Before this, England was widely referred to as ''the land without music" but in a very real sense, .Lionel Tertis was one of the pioneers who, through his artistry of the viola, led the way to the renaissance of music in England in the twentieth century.

MUSICAL EXOTICISM EXPLORED IN PIANO WORKS FROM THE EIGHTEENTH CENTURY THROUGH THE EARLY TWENTIETH CENTURY

Musical exoticism is the evocation of a culture different from that of the composer. It occurs anytime a composer tries to conjure up the music of a country not his own. Although there have been studies of exoticism in the piano works of an individual composer, namely Debussy, there has not been a comprehensive study of musical exoticism in the piano literature as a whole. Upon chronological examination of the piano repertoire, general trends exhibiting exoticism become evident. The first general trend is the emergence of the Turkish style (alia turca) in the eighteenth century. Turkish style soon transmuted to the Hungarian-Gypsy style (all 'ongarese or style hongrois). [In Beethoven's Op. 129, it is alia ingharese.] Composers often alternated between the two styles even in the same composition. By the late nineteenth century, style hongrois was firmly entrenched in the musical language of Austro-German composers, as seen in the works of Brahms. In the nineteenth century, composers turned to the Middle East, North Africa and Spain for inspiration. In particular are several compositions emulating Spanish dance music, culminating in the Spanish works of Debussy and Ravel. The gamelans from Indonesia and objects from the Far East of Japan and China, brought by advances in trade and transportation, captivated the imagination of composers at the turn of the twentieth century. Also in the early twentieth century, composers tried emulating dance and jazz music coming from the Americas, such as the cakewalk, minstrelsy, and the blues. One sees the ever widening sphere of exotic inspiration for western music composers: from the Turkish invasions to the traveling Gypsies of Hungary; to the captivating dance rhythms, soulful cante jondo sections, and guitar flourishes of Spain; expanding further to the far reaches of Asia and the jazzy rhythms of the Americas. This performance dissertation consists of three recitals presented at the University of Maryland, and is documented on compact disc recordings which are housed within the University of Maryland Library System. The recordings present the music of Balakirev, Beethoven, Brahms, Chopin, Debussy, Haydn, Hummel, Milhaud, Moszkowski, Mozart, Ravel, and Schubert.

FROM THE AETHIOPICA TO THE RENAISSANCE: RECOVERING A STAGE TRADITION OF POSITIVE REPRESENTATION OF AFRICANS IN EARLY MODERN ENGLAND

This dissertation looks at the connection between Heliodorus's fifth-century prose romance, An Aethiopian History, certain Renaissance texts, and how these texts helped influence an alternate representation of Africans in the early modern world. Through their portrayals of Africans, early modern English playwrights frequently give the impression that Africans, especially black Africans, were people without accomplishments, without culture. Previously, however, this was not the case. Africans were depicted with dignity, as a tradition existed for this kind of representation--and Renaissance Europe had long been acquainted with the achievements of Africans, dating back to antiquity. As the source of several lost plays, the Aethiopica is instrumental in dramatizing Africans favorably, especially on the early modern stage, and helped shape a stage tradition that runs alongside the stereotyping of Africans. This Heliodoran tradition can be seen in works of Greene, Heywood, Jonson, Shakespeare, and others in the motifs of crosscultural and transracial romance, male and female chastity, racial metamorphosis, lost or abandoned babies, wandering heroes, and bold heroines. In Jonson's Masque of Blackness and Masque of Beauty, I establish a connection between these two masques and Heliodorus's Aethiopica and argue for a Heliodoran stage tradition implicit in both masques through the conceit of blanching. In The English Moore, I explore how Richard Brome uses the Heliodoran and Jonsonian materials to create a negative quality of blackness that participates in the dramatic tradition of the degenerate African on the English Renaissance stage. With Othello, I contend that it is a drama that can be seen in the Heliodoran tradition by stressing certain motifs found in the play that derives from the Aethiopica. Reading Othello this way provides us with a more layered and historicized interpretation of Shakespeare's protagonists. Othello's nationality and faith make his exalted position in Venice and the Venetian army credible and logical. His nobility and heroic status become more sharply defined, giving us a fuller understanding of the emphasis he places on chastity--both for himself and for Desdemona. Instead of a traditional, compliant, and submissive Desdemona, a courageous, resourceful, witty, and pure heroine emerges--one who lives by the dictates of her conscience than by the constraints of societal norms. Recovering the tradition of positive portrayal of Africans that originated from the Aethiopica necessitated an examination of eleven plays that I contend helped to frame the dramatic tradition under investigation. Six of these plays are continental dramas, and five are English. Although three of the English plays are lost and the other two are seventeenth-century dramas, their titles and names of their protagonists, like those of the six extant continental plays, share the names of Heliodorus's hero and heroine, making an exploration of the continental plays imperative to facilitate their use as paradigms in reconstructing the three lost English plays. These continental dramas show that plays whose titles derive from the Aethiopica itself or reflect the names of its major characters follow Heliodorus's text closely, enabling an investigation of the Heliodoran tradition on the early modern English stage. Recovering the Heliodoran tradition adds to the exploration of racial politics and the understanding of the dramatic tradition that constrained and enabled Renaissance playwrights' representation of race and gender.

Early clopidogrel versus prasugrel use among contemporary STEMI and NSTEMI patients in the US: insights from the National Cardiovascular Data Registry.

BACKGROUND: P2Y12 antagonist therapy improves outcomes in acute myocardial infarction (MI) patients. Novel agents in this class are now available in the US. We studied the introduction of prasugrel into contemporary MI practice to understand the appropriateness of its use and assess for changes in antiplatelet management practices. METHODS AND RESULTS: Using ACTION Registry-GWTG (Get-with-the-Guidelines), we evaluated patterns of P2Y12 antagonist use within 24 hours of admission in 100 228 ST elevation myocardial infarction (STEMI) and 158 492 Non-ST elevation myocardial infarction (NSTEMI) patients at 548 hospitals between October 2009 and September 2012. Rates of early P2Y12 antagonist use were approximately 90% among STEMI and 57% among NSTEMI patients. From 2009 to 2012, prasugrel use increased significantly from 3% to 18% (5% to 30% in STEMI; 2% to 10% in NSTEMI; P for trend <0.001 for all). During the same period, we observed a decrease in use of early but not discharge P2Y12 antagonist among NSTEMI patients. Although contraindicated, 3.0% of patients with prior stroke received prasugrel. Prasugrel was used in 1.9% of patients ≥75 years and 4.5% of patients with weight <60 kg. In both STEMI and NSTEMI, prasugrel was most frequently used in patients at the lowest predicted risk for bleeding and mortality. Despite lack of supporting evidence, prasugrel was initiated before cardiac catheterization in 18% of NSTEMI patients. CONCLUSIONS: With prasugrel as an antiplatelet treatment option, contemporary practice shows low uptake of prasugrel and delays in P2Y12 antagonist initiation among NSTEMI patients. We also note concerning evidence of inappropriate use of prasugrel, and inadequate targeting of this more potent therapy to maximize the benefit/risk ratio.

Transgenerational Effects of Early Life Starvation on Growth, Reproduction, and Stress Resistance in Caenorhabditis elegans.

Starvation during early development can have lasting effects that influence organismal fitness and disease risk. We characterized the long-term phenotypic consequences of starvation during early larval development in Caenorhabditis elegans to determine potential fitness effects and develop it as a model for mechanistic studies. We varied the amount of time that larvae were developmentally arrested by starvation after hatching ("L1 arrest"). Worms recovering from extended starvation grew slowly, taking longer to become reproductive, and were smaller as adults. Fecundity was also reduced, with the smallest individuals most severely affected. Feeding behavior was impaired, possibly contributing to deficits in growth and reproduction. Previously starved larvae were more sensitive to subsequent starvation, suggesting decreased fitness even in poor conditions. We discovered that smaller larvae are more resistant to heat, but this correlation does not require passage through L1 arrest. The progeny of starved animals were also adversely affected: Embryo quality was diminished, incidence of males was increased, progeny were smaller, and their brood size was reduced. However, the progeny and grandprogeny of starved larvae were more resistant to starvation. In addition, the progeny, grandprogeny, and great-grandprogeny were more resistant to heat, suggesting epigenetic inheritance of acquired resistance to starvation and heat. Notably, such resistance was inherited exclusively from individuals most severely affected by starvation in the first generation, suggesting an evolutionary bet-hedging strategy. In summary, our results demonstrate that starvation affects a variety of life-history traits in the exposed animals and their descendants, some presumably reflecting fitness costs but others potentially adaptive.

New World Gold Cultural Anxiety and Monetary Disorder in Early Modern Spain

Elvira Vilches examines economic treatises, stories of travel and conquest, moralist writings, fiction, poetry, and drama to reveal that New World gold ultimately became a problematic source of power that destabilized Spain’s sense of ...