An alphavirus vector overcomes the presence of neutralizing antibodies and elevated numbers of Tregs to induce immune responses in humans with advanced cancer.

Therapeutic anticancer vaccines are designed to boost patients' immune responses to tumors. One approach is to use a viral vector to deliver antigen to in situ DCs, which then activate tumor-specific T cell and antibody responses. However, vector-specific neutralizing antibodies and suppressive cell populations such as Tregs remain great challenges to the efficacy of this approach. We report here that an alphavirus vector, packaged in virus-like replicon particles (VRP) and capable of efficiently infecting DCs, could be repeatedly administered to patients with metastatic cancer expressing the tumor antigen carcinoembryonic antigen (CEA) and that it overcame high titers of neutralizing antibodies and elevated Treg levels to induce clinically relevant CEA-specific T cell and antibody responses. The CEA-specific antibodies mediated antibody-dependent cellular cytotoxicity against tumor cells from human colorectal cancer metastases. In addition, patients with CEA-specific T cell responses exhibited longer overall survival. These data suggest that VRP-based vectors can overcome the presence of neutralizing antibodies to break tolerance to self antigen and may be clinically useful for immunotherapy in the setting of tumor-induced immunosuppression.

Qualitative analysis of the interdisciplinary interaction between data analysis specialists and novice clinical researchers.

BACKGROUND: The inherent complexity of statistical methods and clinical phenomena compel researchers with diverse domains of expertise to work in interdisciplinary teams, where none of them have a complete knowledge in their counterpart's field. As a result, knowledge exchange may often be characterized by miscommunication leading to misinterpretation, ultimately resulting in errors in research and even clinical practice. Though communication has a central role in interdisciplinary collaboration and since miscommunication can have a negative impact on research processes, to the best of our knowledge, no study has yet explored how data analysis specialists and clinical researchers communicate over time. METHODS/PRINCIPAL FINDINGS: We conducted qualitative analysis of encounters between clinical researchers and data analysis specialists (epidemiologist, clinical epidemiologist, and data mining specialist). These encounters were recorded and systematically analyzed using a grounded theory methodology for extraction of emerging themes, followed by data triangulation and analysis of negative cases for validation. A policy analysis was then performed using a system dynamics methodology looking for potential interventions to improve this process. Four major emerging themes were found. Definitions using lay language were frequently employed as a way to bridge the language gap between the specialties. Thought experiments presented a series of "what if" situations that helped clarify how the method or information from the other field would behave, if exposed to alternative situations, ultimately aiding in explaining their main objective. Metaphors and analogies were used to translate concepts across fields, from the unfamiliar to the familiar. Prolepsis was used to anticipate study outcomes, thus helping specialists understand the current context based on an understanding of their final goal. CONCLUSION/SIGNIFICANCE: The communication between clinical researchers and data analysis specialists presents multiple challenges that can lead to errors.

Homeostatic imbalance of purine catabolism in first-episode neuroleptic-naïve patients with schizophrenia.

BACKGROUND: Purine catabolism may be an unappreciated, but important component of the homeostatic response of mitochondria to oxidant stress. Accumulating evidence suggests a pivotal role of oxidative stress in schizophrenia pathology. METHODOLOGY/PRINCIPAL FINDINGS: Using high-pressure liquid chromatography coupled with a coulometric multi-electrode array system, we compared 6 purine metabolites simultaneously in plasma between first-episode neuroleptic-naïve patients with schizophrenia (FENNS, n = 25) and healthy controls (HC, n = 30), as well as between FENNS at baseline (BL) and 4 weeks (4w) after antipsychotic treatment. Significantly higher levels of xanthosine (Xant) and lower levels of guanine (G) were seen in both patient groups compared to HC subjects. Moreover, the ratios of G/guanosine (Gr), uric acid (UA)/Gr, and UA/Xant were significantly lower, whereas the ratio of Xant/G was significantly higher in FENNS-BL than in HC. Such changes remained in FENNS-4w with exception that the ratio of UA/Gr was normalized. All 3 groups had significant correlations between G and UA, and Xan and hypoxanthine (Hx). By contrast, correlations of UA with each of Xan and Hx, and the correlation of Xan with Gr were all quite significant for the HC but not for the FENNS. Finally, correlations of Gr with each of UA and G were significant for both HC and FENNS-BL but not for the FENNS-4w. CONCLUSIONS/SIGNIFICANCE: During purine catabolism, both conversions of Gr to G and of Xant to Xan are reversible. Decreased ratios of product to precursor suggested a shift favorable to Xant production from Xan, resulting in decreased UA levels in the FENNS. Specifically, the reduced UA/Gr ratio was nearly normalized after 4 weeks of antipsychotic treatment. In addition, there are tightly correlated precursor and product relationships within purine pathways; although some of these correlations persist across disease or medication status, others appear to be lost among FENNS. Taken together, these results suggest that the potential for steady formation of antioxidant UA from purine catabolism is altered early in the course of illness.

Global fire emissions and the contribution of deforestation, savanna, forest, agricultural, and peat fires (1997-2009)

New burned area datasets and top-down constraints from atmospheric concentration measurements of pyrogenic gases have decreased the large uncertainty in fire emissions estimates. However, significant gaps remain in our understanding of the contribution of deforestation, savanna, forest, agricultural waste, and peat fires to total global fire emissions. Here we used a revised version of the Carnegie-Ames-Stanford-Approach (CASA) biogeochemical model and improved satellite-derived estimates of area burned, fire activity, and plant productivity to calculate fire emissions for the 1997-2009 period on a 0.5° spatial resolution with a monthly time step. For November 2000 onwards, estimates were based on burned area, active fire detections, and plant productivity from the MODerate resolution Imaging Spectroradiometer (MODIS) sensor. For the partitioning we focused on the MODIS era. We used maps of burned area derived from the Tropical Rainfall Measuring Mission (TRMM) Visible and Infrared Scanner (VIRS) and Along-Track Scanning Radiometer (ATSR) active fire data prior to MODIS (1997-2000) and estimates of plant productivity derived from Advanced Very High Resolution Radiometer (AVHRR) observations during the same period. Average global fire carbon emissions according to this version 3 of the Global Fire Emissions Database (GFED3) were 2.0 PgC year-1 with significant interannual variability during 1997-2001 (2.8 Pg Cyear-1 in 1998 and 1.6 PgC year-1 in 2001). Globally, emissions during 2002-2007 were rela-tively constant (around 2.1 Pg C year-1) before declining in 2008 (1.7 Pg Cyear-1) and 2009 (1.5 PgC year-1) partly due to lower deforestation fire emissions in South America and tropical Asia. On a regional basis, emissions were highly variable during 2002-2007 (e.g., boreal Asia, South America, and Indonesia), but these regional differences canceled out at a global level. During the MODIS era (2001-2009), most carbon emissions were from fires in grasslands and savannas (44%) with smaller contributions from tropical deforestation and degradation fires (20%), woodland fires (mostly confined to the tropics, 16%), forest fires (mostly in the extratropics, 15%), agricultural waste burning (3%), and tropical peat fires (3%). The contribution from agricultural waste fires was likely a lower bound because our approach for measuring burned area could not detect all of these relatively small fires. Total carbon emissions were on average 13% lower than in our previous (GFED2) work. For reduced trace gases such as CO and CH4, deforestation, degradation, and peat fires were more important contributors because of higher emissions of reduced trace gases per unit carbon combusted compared to savanna fires. Carbon emissions from tropical deforestation, degradation, and peatland fires were on average 0.5 PgC year-1. The carbon emissions from these fires may not be balanced by regrowth following fire. Our results provide the first global assessment of the contribution of different sources to total global fire emissions for the past decade, and supply the community with an improved 13-year fire emissions time series. © 2010 Author(s).

Integrated analysis of CANVAS 1 and 2: phase 3, multicenter, randomized, double-blind studies to evaluate the safety and efficacy of ceftaroline versus vancomycin plus aztreonam in complicated skin and skin-structure infection.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of complicated skin and skin-structure infection (cSSSI). Increasing antimicrobial resistance in cSSSI has led to a need for new safe and effective therapies. Ceftaroline was evaluated as treatment for cSSSI in 2 identical phase 3 clinical trials, the pooled analysis of which is presented here. The primary objective of each trial was to determine the noninferiority of the clinical cure rate achieved with ceftaroline monotherapy, compared with that achieved with vancomycin plus aztreonam combination therapy, in the clinically evaluable (CE) and modified intent-to-treat (MITT) patient populations. METHODS: Adult patients with cSSSI requiring intravenous therapy received ceftaroline (600 mg every 12 h) or vancomycin plus aztreonam (1 g each every 12 h) for 5-14 days. RESULTS: Of 1378 patients enrolled in both trials, 693 received ceftaroline and 685 received vancomycin plus aztreonam. Baseline characteristics of the treatment groups were comparable. Clinical cure rates were similar for ceftaroline and vancomycin plus aztreonam in the CE (91.6% vs 92.7%) and MITT (85.9% vs 85.5%) populations, respectively, as well as in patients infected with MRSA (93.4% vs 94.3%). The rates of adverse events, discontinuations because of an adverse event, serious adverse events, and death also were similar between treatment groups. CONCLUSIONS: Ceftaroline achieved high clinical cure rates, was efficacious against cSSSI caused by MRSA and other common cSSSI pathogens, and was well tolerated, with a safety profile consistent with the cephalosporin class. Ceftaroline has the potential to provide a monotherapy alternative for the treatment of cSSSI. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00424190 for CANVAS 1 and NCT00423657 for CANVAS 2.

The life of leaders: an intensive health program for clergy.

Clergy suffer from chronic disease rates that are higher than those of non-clergy. Health interventions for clergy are needed, and some exist, although none to date have been described in the literature. Life of Leaders is a clergy health intervention designed with particular attention to the lifestyle and beliefs of United Methodist clergy, directed by Methodist LeBonheur Healthcare Center of Excellence in Faith and Health. It consists of a two-day retreat of a comprehensive executive physical and leadership development process. Its guiding principles include a focus on personal assets, multi-disciplinary, integrated care, and an emphasis on the contexts of ministry for the poor and community leadership. Consistent with calls to intervene on clergy health across multiple ecological levels, Life of Leaders intervenes at the individual and interpersonal levels, with potential for congregational and religious denominational change. Persons wishing to improve the health of clergy may wish to implement Life of Leaders or borrow from its guiding principles.

Cysteine proteinase-1 and cut protein isoform control dendritic innervation of two distinct sensory fields by a single neuron.

Dendrites often exhibit structural changes in response to local inputs. Although mechanisms that pattern and maintain dendritic arbors are becoming clearer, processes regulating regrowth, during context-dependent plasticity or after injury, remain poorly understood. We found that a class of Drosophila sensory neurons, through complete pruning and regeneration, can elaborate two distinct dendritic trees, innervating independent sensory fields. An expression screen identified Cysteine proteinase-1 (Cp1) as a critical regulator of this process. Unlike known ecdysone effectors, Cp1-mutant ddaC neurons pruned larval dendrites normally but failed to regrow adult dendrites. Cp1 expression was upregulated/concentrated in the nucleus during metamorphosis, controlling production of a truncated Cut homeodomain transcription factor. This truncated Cut, but not the full-length protein, allowed Cp1-mutant ddaC neurons to regenerate higher-order adult dendrites. These results identify a molecular pathway needed for dendrite regrowth after pruning, which allows the same neuron to innervate distinct sensory fields.

ARAB MUSICIANS IN WASHINGTON, D.C. AREA: ETHNICITY AND IDENTITY

Musicians living in the Arab Diaspora around the Washington, D.C. metro area are a small group of multi-faceted individuals with significant contributions and intentions to propagate and disseminate their music. Various levels of identity are discussed and analyzed, including self-identity, group/ collective identity, and Arab ethnic identity. The performance and negotiation of Arab ethnic identity is apparent in selected repertoire, instrumentation, musical style, technique and expression, shared conversations about music, worldview on Arabic music and its future. For some musicians, further evidence of self-construction of one's ethnic identity entails choice of name, costume, and venue. Research completed is based on fieldwork, observations, participant-observations, interviews, and communications by phone and email. This thesis introduces concepts of Arabic music, discusses recent literature, reveals findings from case studies on individual Arab musicians and venues, and analyzes Arab identity and ethnicity in relation to particular definitions of identity found in anthropological and ethnomusicological writings. Musical lyrics, translations, transcriptions, quotes, discussions, analyses, as well as charts and diagrams of self-identity analyses are provided as evidence of the performance and negotiation of Arab identity.

CHASING THE SINGERS: THE TRANSITION OF LONG-SONG (URTYN DUU) IN POST-SOCIALIST MONGOLIA

Long-song (Urtyn duu) is a prominent Mongolian traditional folk song genre that survived throughout the socialist period (1921-1990) and throughout the political transformation of Mongolia from socialism to democratic capitalism after the Soviet Union was dismantled and terminated its aid to Mongolia in 1990. This dissertation, based on research conducted from 2006 to 2010, presents and investigates the traces of singers' stories and memories of their lives, songs, and singing, through the lens of the discourse on change and continuity in, and as, folk tradition. During the socialist period, this genre was first considered backward, and was then subtly transformed into an urban national style, with the formation of a boundary between professionalism and amateurism among long-song singers and with selective performance of certain songs and styles. This boundary was associated with politics and ideology and might be thought to have ended when the society entered its post-socialist period. However, the long-song genre continued to play a political role, with different kinds of political meaning one the one hand and only slight musical modification on the other. It was now used to present a more nostalgic and authentic new Mongolian identity in the post-socialist free market. Through my investigation, I argue that the historical transition of Mongolia encompassed not merely political or economic shifts, but also a deeper transformation that resulted in new cultural forms. Long-song provides a good case study of the complicated process of this cultural change.

Olfactory cuing of autobiographical memory.

In Experiment 1, subjects were presented with either the odors or the names of 15 common objects. In Experiment 2, subjects were presented with either the odors, photographs, or names of 16 common objects. All subjects were asked to describe an autobiographical memory evoked by each cue, to date each memory, and to rate each memory on vividness, pleasantness, and the number of times that the memory had been thought of and talked about prior to the experiment. Compared with memories evoked by photographs or names, memories evoked by odors were reported to be thought of and talked about less often prior to the experiment and were more likely to be reported as never having been thought of or talked about prior to the experiment. No other effects were consistently found, though there was a suggestion that odors might evoke more pleasant and emotional memories than other types of cues. The relation of these results to the folklore concerning olfactory cuing is discussed.

Nutritional control of mRNA isoform expression during developmental arrest and recovery in C. elegans.

Nutrient availability profoundly influences gene expression. Many animal genes encode multiple transcript isoforms, yet the effect of nutrient availability on transcript isoform expression has not been studied in genome-wide fashion. When Caenorhabditis elegans larvae hatch without food, they arrest development in the first larval stage (L1 arrest). Starved larvae can survive L1 arrest for weeks, but growth and post-embryonic development are rapidly initiated in response to feeding. We used RNA-seq to characterize the transcriptome during L1 arrest and over time after feeding. Twenty-seven percent of detectable protein-coding genes were differentially expressed during recovery from L1 arrest, with the majority of changes initiating within the first hour, demonstrating widespread, acute effects of nutrient availability on gene expression. We used two independent approaches to track expression of individual exons and mRNA isoforms, and we connected changes in expression to functional consequences by mining a variety of databases. These two approaches identified an overlapping set of genes with alternative isoform expression, and they converged on common functional patterns. Genes affecting mRNA splicing and translation are regulated by alternative isoform expression, revealing post-transcriptional consequences of nutrient availability on gene regulation. We also found that phosphorylation sites are often alternatively expressed, revealing a common mode by which alternative isoform expression modifies protein function and signal transduction. Our results detail rich changes in C. elegans gene expression as larvae initiate growth and post-embryonic development, and they provide an excellent resource for ongoing investigation of transcriptional regulation and developmental physiology.

A Comparative Study of the Chinese Trickster Hero Sun Wukong

Sun Wukong is a fictional hero from the Chinese classic The Journey to the West. As a well-known trickster, Wukong has a lot of similarities with several other tricksters around the world. In order to analyze him, I try to explain both his similarities with, and differences from, other tricksters, especially in the Ancient Greek folklore and myth traditions. The first half of the paper focuses on the general characteristics of tricksters. As a very distinctive group in global mythology, tricksters have particular features. The definition and symbolization of tricksters are illustrated by comparing Wukong and major Greek tricksters, such as Hermes, Odysseus, and Prometheus. The second part of the paper is concentrated on the heroic features of tricksters and the cultural values reflected in the Wukong narrative. How tricksters become cultural heroes is the main theme of Chapter Three. I explain their evolution by elaborating on the change in their nature mentioned in the second chapter. The fourth chapter illustrates the reason why Wukong is an East Asian cultural hero.I explore the personalities of Wukong and see how they fit the dominant philosophy and cultural values of the region. The last chapter briefly shows how popular Wukong is in Chinese and the entire East Asian culture.

Polish Violin Music in the 20th and 21st Century

The purpose of this dissertation is to promote Polish violin music written in the 20th and 21st Century. My recitals included many lesser-known compositions and composers which I strongly believe deserve to be better known and more often performed. The search and preparation of those pieces, for which recordings and music scores are not easily found, was a very exciting and stimulating process. Much Polish music written in the 20th and 21st Century is interesting, expressive, beautiful, and deserves to be more often performed. Performing 20th and 21st Century music opens new perspectives in two directions: musically and technically. Performer and listener are, in many cases, unbound from tonality. Composers are looking for new sonorities and exploring such performing techniques as varieties of harmonics, quarter tones, extreme dynamics, complex rhythms, and usage of a wide range of registers. An important part of Polish music is Polish folklore. The little town of Zakopane is known for Polish traditional clothing, food, architecture, dance and music. Also, most prominent Polish luthiers including Wojciech Topa, whose instrument I am playing, have been making their instruments in Zakopane. This little town in the Tatras Mountain has been an inspiration for many Polish artists including Iwaszkiewicz, Witkacy, Karłowicz, and Szymanowski. Those composers used such folklore elements as folk scales, popular tunes, and imitations of the sound of the folk band with characteristic folk dance rhythms. Other musical genres where folk elements are strongly present are the compositions dedicated to young musicians, with a specifically educational purpose. Among composers who wrote educational music were Grażyna Bacewicz, Witold Lutosławski, and Henryk Mikołaj Górecki. This approach makes the works more easily understood by young performers and, at the same time, broadens their understanding of Polish culture and prepares them for the challenges of contemporary music. This has been an exciting project for me because, on the one hand, it allowed me the challenge of performing compositions that are lesser-known and often consist of musical language new to me while, on the other, it brought me back to my roots and the country of my mother tongue.

Control microbiano de la chinche del tallo del arroz, Tibraca limbativentris Stal. 1860 (Hemiptera: Pentatomidae) con hongos entomopatógenos

El cultivo del arroz es una de las principales actividades productivas en el Nordeste Argentino, el cual se ve afectado por diferentes plagas que reducen su rendimiento y calidad. Entre ellas, la chinche del tallo, Tibraca limbativentris es una de las plagas principales. Para su control, el uso de agroquímicos es generalizado, por su conveniencia y eficiencia. Sin embargo, el mal uso de los productos fitosanitarios está ocasionando problemas al ambiente, lo que lleva a la búsqueda de nuevas tecnologías, reduciendo al mínimo los riesgos al ambiente y a la salud humana en particular. En el presente estudio se evalúa el uso de hongos entomopatógenos como una alternativa para reducir la población de T. limbativentris. Se realizaron muestreos en diversas zonas arroceras en búsqueda de cepas nativas de hongos entomopatógenos, lográndose aislar 11 cepas de adultos de esta chinche. A través de bioensayos se evaluaron 32 cepas de hongos entomopatógenos sobre adultos y dos de ellas causaron la muerte del 100 por ciento de los mismos. Se seleccionó la cepa Ma 72 de Metarhizium anisopliae y se evaluó la compatibilidad con diversos herbicidas usados frecuentemente en la producción de arroz. Se logró producir la cepa sobre diversos sustratos en fermentación en medio sólido (FMS4), destacándose el arroz blanco quebrado, sobre el cual se obtuvo 3,8 x 109 conidios/gr de sustrato. Se evaluaron diferentes tipos de formulaciones experimentales durante 100 días y la viabilidad se mantuvo sólo bajo condiciones de refrigeración (6 °C). Se evalúo la eficiencia de diversos formulados experimentales sobre adultos de T. limbativentris en condiciones de invernáculo, logrando un control satisfactorio (entre 56 y 77 por ciento de mortalidad) a los 30 días. Se concluyó que la cepa Ma 72 de M. anisopliae sería una herramienta promisora para su empleo en el control microbiano de la chinche del tallo T. limbativentris y podrían incluirse como parte de un programa de Manejo Integrado de plagas en arroz