Journal articles on the topic 'Cultic acts'

AbstractDespite a lack of evidence for the practice of sacred prostitution in the ancient Middle East, scholars have continued to understand the wordqdešɔin Hosea 4:14 to denote a female officiant who performed sexual acts in a cultic setting. This article argues that the understanding of theqdešɔas a cultic prostitute has appealed to interpreters for over two millennia because the Hebrew word has a semantic range that includes both female cultic functionaries and prostitutes. The lexeme denotes a class of women who are employed outside of the patrimonial estate, including priestesses or prostitutes (but never both at the same time). When the prophet indicts the Israelites for sacrificing with qdešot, he deploys a pun that strengthens his metaphor of Israel as a wayward woman.

The city of Ephesus experienced a marked civic transformation in Late Antiquity. After having centered its settlements and economic fortunes on its proximity to a deep-water harbor for over a millenium, late antique Ephesus gradually shifted to an inland, fortified settlement on Ayasoluk Hill. While several factors undoubtedly informed this civic reorientation, the most commonly cited impetus for Ephesus’s late antique reorientation was the infilling of its deep-water harbor. This article argues that, in addition to this environmental cause, an important cultural shift correspondingly informed Ephesus’s late antique reconfigurations. Namely, the emergence and development of the tomb of John on Ayasoluk Hill, informed by an array of literary legends associating the apostle with the city, increasingly positioned this site as a cultic and economic focal point in Late Antiquity. This article argues that an important early strand in this cultural fabric was the Acts of John, a collection of apocryphal tales that narrate John’s exploits in Ephesus. Significantly, the Acts of John articulates a “counter-cartography” that disassociates Christian identity from prominent Ephesian cultic sites and accentuates the importance of spaces “outside the city” of Ephesus, including and especially the tomb of John. Through its own circulation as well as its influence on later Johannine narratives, the early Acts of John helped inform a shift in the cultural cartographies of Ephesus, where Greco-Roman polytheistic spaces were gradually devalued in favor of Christian sites, the tomb of John on Ayasoluk chief among them.

Scholars have frequently underplayed the significance of the emperors within actual social and religious life in cities of the Roman empire and have portrayed imperial cults as predominantly political, lacking in religious dimensions. However, this view of imperial cults is misguided and acts as an obstacle to understanding the nature and significance of these cults at the local level. A fresh study of associations (local social-religious groups) in Ephesus helps to clarify the significance of emperors with respect to social, political and religious facets of life. There were two main interconnected ways in which emperors played a role in social and religious life within associations: in regard to networks of benefaction and with respect to cultic activities.

Hoard finds appear throughout the European Bronze Age with distinct chronological and chorological peaks. While there is some consensus on seeing hoards as an expression of cultic behaviour, the large ‘scrap metal' hoards in particular still provoke interpretations as raw material collected for recycling. With socketed axes whose sockets were intentionally filled with deliberately fragmented metalwork, Hansen (1996–1998) has pointed out a group of finds that could be crucial to a better understanding of ‘scrap’ hoards. Using the finds from the Carpathian Basin as a case study, a dual biographical approach is applied to this group. A close look at the complex use-life of the objects themselves, as well as an attempt at re-integrating them into the local history of hoarding, leads to the conclusion that they constitute single acts of dedication in larger contexts. “Scrap hoards’” can thus be understood as long-term accumulations of votive objects and can be integrated into the social practice of Bronze Age hoarding.

While a biblical doctrine of sin requires the honest and careful assessment of the complexity and plurality of the biblical witness,2 especially with regard to the relationship of the two Testaments, scholarship often draws lines of demarcation between the two Testaments too sharply. Ancient Israel’s priests devoted significant attention to the “objective” quality of wrong done as a pastoral problem, for example. Leviticus establishes that “unintentional sin” covers the whole gamut of behaviors short of willful sin that can result in terrible injury and harm. Indeed, the priests so consistently held the notion that wrong inheres in a situation, regardless of the intention of the actor, that they could use the language of sin to discuss skin diseases (Lev 14:1–32) and mold in houses (Lev 14:33–53). Israel’s priests did not speculate as to the precise point along the spectrum of willfulness and inadvertence at which one becomes morally culpable in the legal sense. Instead, their approach was much more pastoral: whatever the psychological and ethical dynamics preceding and underlying a wrong, the priests saw their role primarily in terms of healing, restoration, and restitution. Jesus and James expanded the priestly notion of sin as an objective reality to include intention as a category in the discussion of sin, but did not make it definitive of sin. Although the Gospels preserve no other discourse of Jesus even impinging on the subject of the concrete reality of sin, Jesus’ behaviors, especially instances when he healed without assigning blame or seeking repentance first, manifest his priestly concern for correcting inherent wrongness, for restoring rightness. Following Jesus, the priests’ view that any disorder threatens the harmony of the cultic community can supply useful and pertinent raw material for Christian theology and ethics today.

AbstractDespite the anthropological identification of slavery as an anti-kinship structure, some New Testament scholars have attempted to "kin-ify" the relations between slaveholders and slaves, that is, to interpret slavery as a fictive kinship structure. Commentators on Acts of the Apostles, for example, are likely to accept the patriarchal or matriarchal right of householders to enforce decisions concerning the cultic practices of household slaves. By suggesting that the Spirit responds to the invitations of slaveholders, household by patriarchal household, Acts treats enslaved members of households as dependent bodies subjected to the intellectual and spiritual authority of slaveholders. By accepting uncritically Luke's portrait of the growth of the church, household by patriarchal household, commentators unwittingly buy into a family plot that legitimates the slaveholder's preferred vision of the household. Drawing on sources as disparate as Egyptian papyri of the Roman era and personal family history, this article challenges attempts to subsume relationships of slavery within the warm circle of the family. At the same time, the article warns against sentimental depictions of maternal and other family ties. In the first century as in the twenty-first century, the family could be a locus of exploitation and alienation. The natal alienation at the heart of the ancient slave experience is ultimately intertwined with the forms of alienation inherent within families themselves. It is not that relations of slavery are warmer than we might expect, but rather that relations between even the closest of kin can be more exploitative than we want to admit.

Summary A mithraeum always has long benches, which were called praesepiae, “places where cattle are fed in a stall” (CIMRM 233). The name is inappropriate for a dining room, which was usually called, instead, triclinium. Mithraeum is the current modern name, whereas the ancients called it spelaeum, antrum, templum. Another important name was Leonteum, which was not a separate cultic place for Leones only, because Porphyry states that the members of a Mithraic community were the Leones and the servants were called Korakes, the Ravens (Porphyr. de abst. 4. 16). The Mithraic menu apparently consisted of meat rather than of vegetables, even though one should take into account the fact that bones are better preserved than vegetables in an archaeological site, and therefore they are often published, whereas vegetal remains had never been investigated by means of chemical analyses. Lions are notoriously carnivorous and the praesepiae had to be filled with meat for the Leones. The initiation of Leones was supposed to be dry and fiery (Tert. Adv. Marcionem I 13), and we are also told that the Mithraic Leones avoided water for their purifications and washed their hands with honey (Porph. De antro 15–16). Moreover, a lion and a snake are often depicted on Mithraic reliefs as going to drink from a crater. It is possible to get some information from those facts about what Leones were used to drinking during their symposia: they were thirsty but their drink could not be water, but eventually, wine was permitted. Iustin. Apol. I 66 speaks of a cup of water, but only to mention some ritual acts during initiations and not during symposia.

In the first part of this article I summarize the ongoing historiographical debate over Michel Foucault's theory of the nineteenth-century medical ‘invention’ of homosexuality, as it was formulated in the 1976 first volume of The History of Sexuality, The Will to Knowledge. Starting from the now-outdated conflict between ‘essentialists’ and ‘social constructionists’, I underline the ‘blind spots’ of the Foucauldian narrative as highlighted by postcolonial, feminist and queer criticisms. In the second part, I shift to the historiography of the early modern Iberian and Colonial world. Even though a lot of work in this field has already been done, I think that a full comprehension of the connections between this research and the international debate on the history of gender and sexual transgressions is still lacking. Through the analysis of this literature, I propose a revision of Foucault's account, questioning the idea of the nineteenth-century ‘great paradigm shift’. On the one hand, these studies address the long-term genealogy of issues that has fully ripened in the nineteenth century. On the other, they confirm the coexistence in past societies of a multiplicity of understandings of sexual behaviors that questions the hypothesis of a succession of coherent and homogeneous epistemological patterns.

Michel Foucault's The History of Sexuality has been the subject of debate among historians for decades. More specifically, his assertion, ‘the sodomite was a temporary aberration, the homosexual was now a species,’ has been used to support an ‘acts-to-identity’ theory that locates in the late-nineteenth century a shift in thinking about sexuality. The author argues that a re-reading of Foucault shifts the focus of historical inquiry from identities towards the process of knowledge creation, allowing for ambiguity that the concept ‘identity’ might foreclose. This essay examines the debate and offers a new reading of Foucault based on the work of Lynne Huffer. Finally, the author seeks to centre a source-driven approach in conjunction with The History of Sexuality, providing readings of patients and informants from the work of Richard von Krafft-Ebing and Havelock Ellis.

The relevance of research. One of the most important unsolved problems of cultural studies, religious studies, art history, and history is to determine the time of the origin of religious ideas: that of the beginning of the spiritual evolution of the mankind, which at a certain stage of development begins to master not only the material world but also tries to comprehend the supernatural transcendent reality. The views of scholars regarding the time of the birth of religious beliefs is divided into two opposing points of view. According to one of them, expressed in the works of R. Marett, F. Ratzel, V. Kabo, A. Zubov, religious representations were inherent in the primitive man since the beginning of existence. A serious argument against this version is the fact that art the site of Olduvai culture no object was found that did not have a utilitarian purpose and that could be interpreted as a cult object. However, this fact can be explained by the fact that the rational awareness of the highest supernatural power was preceded by its subconscious (intuitive) sensation, which did not require objectivation in cult objects. Religious ideas were primitive so that they did not need any cult objects. According to other scholars, one can speak of the emergence of religious ideas only from the moment when the cult artefacts appeared; the pre-religious period had lasted until the end of the Mousterian era. However, the discovery of a number of archaeological sites in the second half of the 20th century at the beginning of the 21st century makes it possible to move the beginning of the appearance of Religious beliefs back until the period of the late Acheulean–beginning of Mousterian era.The purpose of the article: to establish the time of the origin and evolution of the earliest religious beliefs associated with the cult of bones, based on the analysis of the most ancient artefacts currently known, which testify to the ritual activities of the primitive man. The considered artefacts lead to the conclusion that the most ancient evidence of the cults of bones belongs to the era of the late Acheulean and Mousterian. Animal bones were among the first objects that the primitive man singled out from the environment as sacred, and endowed with a supernatural ability to revive the lives of animals and humans. Symbolic compositions of bones and signs carved in them became sacred attributes used for magical rites. The first acts of the ritual symbolization marked the emergence of sacred art and magic, which, radically different from the directly useful work, passed into a special plane of connection of men with the supernatural force. The earliest monuments (Torralba, Ambrona, Azykh), which testify to magical actions with bones, date back to about 400–200 thousand years BC. Thus, more than 2 million years passed from the appearance of man (ca. 2.7 million years ago) to the emergence of religious ideas, which required objectification in cult items and the performance of certain rituals. Although it cannot be denied that the intuitive subconscious sense of the supernatural power has been inherent in man since the beginning of his existence, purposefully by cultic magical actions that called on higher powers for help, he began to practice from the period of the late Acheulean. In the Mousterian era, in addition to the cult of bones, the cult of the skull arose as a container of special energy capable of renewing human life. Despite the fact that there are only a few examples of skull burials in the Mousterian period, apart from Mount Circeo, in Zhoukoudian (1929), Ngandonga (1931–1933) and Steingheim (1933), it can be assumed that about 70–50 thousand years ago, along with burials, an undissected body could be another rite of separation of the skull, which as a container of a special vital energy of man was buried in some parts of the caves on piles of bones and stones, just as at about the same time separately buried the skulls of bears in stone boxes and niches in caves of Regurdu, Azykh, Drachenloh, Wildenmannlisloch, and others. Later, with the development of ideas about the soul, the cult of skulls is further developed, based on the realization of the power of the extracorporeal spiritual essence of the revered dead (= ancestors), the concentration of which requires a magical container.

ABSTRACT The V protein of simian virus 5 (SV5) facilitates the ubiquitination and subsequent proteasome-mediated degradation of STAT1. Here we show, by visualizing direct protein-protein interactions and by using the yeast two-hybrid system, that while the SV5 V protein fails to bind to STAT1 directly, it binds directly and independently to both DDB1 and STAT2, two cellular proteins known to be essential for SV5-mediated degradation of STAT1. We also demonstrate that STAT1 and STAT2 interact independently of SV5 V and show that SV5 V protein acts as an adaptor molecule linking DDB1 to STAT2/STAT1 heterodimers, which in the presence of additional accessory cellular proteins, including Cullin 4a, can ubiquitinate STAT1. Additionally, we show that the avidity of STAT2 for V is relatively weak but is significantly enhanced by the presence of both STAT1 and DDB1, i.e., the complex of STAT1, STAT2, DDB1, and SV5 V is more stable than a complex of STAT2 and V. From these studies we propose a dynamic model in which SV5 V acts as a bridge, bringing together a DDB1/Cullin 4a-containing ubiquitin ligase complex and STAT1/STAT2 heterodimers, which leads to the degradation of STAT1. The loss of STAT1 results in a decrease in affinity of binding of STAT2 for V such that STAT2 either dissociates from V or is displaced from V by STAT1/STAT2 complexes, thereby ensuring the cycling of the DDB1 and SV5 V containing E3 complex for continued rounds of STAT1 ubiquitination and degradation.

This paper focuses on sport as panacea for cultism in Nigerian tertiary institutions. The vices that stigmatized the tertiary institutions today are traceable to the uncontrolled behaviour of students. School authorities and concerned government over the years have applied measures to check the excesses of students in tertiary institutions without noticeable success. Sports stand to provide the needed solution to these linger problems of cultism in tertiary institutions. Sports is perceived as wholesome pursuits for students in tertiary institution which channel their thinking and disposition toward worthwhile goal. Sports provide students the opportunity to cultivate sportsmanship qualities, which is necessary for school discipline. The paper focused on the educational values of sports to include self discipline and control, obedience to and co-operation with constituted authorities among others. Similarly, sports provide students with safety value of letting off excessive energies, which ordinarily could have been mischievously channeled towards acts that are opposed to school discipline. The sports programme organization in schools were highlighted the components of a sound sports programmes in Nigerian te rtiary institutions from which students can benefit in building up desirable behaviour were also discussed. Finally, recommendations were made on how participation in sports by students can help solve the problems of cultism activities in tertiary institutions.

Energy poverty as a social problem and the ways of solving this issueThe article is devoted to one of the social problem — fuel poverty, that is diffi culties with meeting energy needs. It provides the discretion of the issue, including the definitions which have been proposed by Brits and Poles. It also contains information about the scale of the problem in Poland in diff erent social groups, identification of the reasons of fuel poverty as well as the possible ways of solving it. The analyses of Polish legal acts related to this issue has been conducted and described.

The family of cullin-RING E3 Ligases (CRLs) and the constitutive photomorphogenesis 9 (COP9) signalosome (CSN) form dynamic complexes that mediate ubiquitylation of 20% of the proteome, yet regulation of their assembly/disassembly remains poorly understood. Inositol polyphosphates are highly conserved signaling molecules implicated in diverse cellular processes. We now report that inositol hexakisphosphate (IP6) is a major physiologic determinant of the CRL–CSN interface, which includes a hitherto unidentified electrostatic interaction between the N-terminal acidic tail of CSN subunit 2 (CSN2) and a conserved basic canyon on cullins. IP6, with an EC50 of 20 nM, acts as an intermolecular “glue,” increasing cullin–CSN2 binding affinity by 30-fold, thereby promoting assembly of the inactive CRL–CSN complexes. The IP6 synthase, Ins(1,3,4,5,6)P5 2-kinase (IPPK/IP5K) binds to cullins. Depleting IP5K increases the percentage of neddylated, active Cul1 and Cul4A, and decreases levels of the Cul1/4A substrates p27 and p21. Besides dysregulating CRL-mediated cell proliferation and UV-induced apoptosis, IP5K depletion potentiates by 28-fold the cytotoxic effect of the neddylation inhibitor MLN4924. Thus, IP5K and IP6 are evolutionarily conserved components of the CRL–CSN system and are potential targets for cancer therapy in conjunction with MLN4924.

Intracellular pathogen infection leads to proteotoxic stress in host organisms. Previously we described a physiological program in the nematodeCaenorhabditis eleganscalled the intracellular pathogen response (IPR), which promotes resistance to proteotoxic stress and appears to be distinct from canonical proteostasis pathways. The IPR is controlled by PALS-22 and PALS-25, proteins of unknown biochemical function, which regulate expression of genes induced by natural intracellular pathogens. We previously showed that PALS-22 and PALS-25 regulate the mRNA expression of the predicted ubiquitin ligase component cullincul-6, which promotes thermotolerance inpals-22mutants. However, it was unclear whether CUL-6 acted alone, or together with other cullin-ring ubiquitin ligase components, which comprise a greatly expanded gene family inC. elegans. Here we use coimmunoprecipitation studies paired with genetic analysis to define the cullin-RING ligase components that act together with CUL-6 to promote thermotolerance. First, we identify a previously uncharacterized RING domain protein in the TRIM family we named RCS-1, which acts as a core component with CUL-6 to promote thermotolerance. Next, we show that the Skp-related proteins SKR-3, SKR-4, and SKR-5 act redundantly to promote thermotolerance with CUL-6. Finally, we screened F-box proteins that coimmunoprecipitate with CUL-6 and find that FBXA-158 and FBXA-75 promote thermotolerance. In summary, we have defined the three core components and two F-box adaptors of a cullin-RING ligase complex that promotes thermotolerance as part of the IPR inC. elegans, which adds to our understanding of how organisms cope with proteotoxic stress.

In genetic screens aimed at understanding drug resistance mechanisms in chronic myeloid leukemia cells, inactivation of the cullin 3 adapter protein-encoding leucine zipper-like transcription regulator 1 (LZTR1) gene led to enhanced mitogen-activated protein kinase (MAPK) pathway activity and reduced sensitivity to tyrosine kinase inhibitors. Knockdown of theDrosophila LZTR1orthologCG3711resulted in a Ras-dependent gain-of-function phenotype. Endogenous human LZTR1 associates with the main RAS isoforms. Inactivation ofLZTR1led to decreased ubiquitination and enhanced plasma membrane localization of endogenous KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog). We propose that LZTR1 acts as a conserved regulator of RAS ubiquitination and MAPK pathway activation. BecauseLZTR1disease mutations failed to revert loss-of-function phenotypes, our findings provide a molecular rationale forLZTR1involvement in a variety of inherited and acquired human disorders.

A maioria dos anticorpos monoclonais (AcMs) já produzidos contra o herpesvírus bovino tipo 1 (BoHV-1) reage com a glicoproteína C (gC), um antígeno abundante e imunodominante presente no envelope viral. Com o objetivo de produzir AcMs com outras especificidades protéicas, antígenos de uma cepa do BoHV-1 defectiva no gene da gC foram utilizados para a imunização de camundongos BALB/c. Após fusão e seleção de 54 hibridomas resistentes ao meio seletivo HAT, foram obtidos três clones (1F1, 2H4 e 4D7) secretores de imunoglobulinas da classe IgG2a, que reagiram com antígenos da cepa homóloga. Os AcMs reagiram com antígenos virais nas técnicas de imunofluorescência (IFA) e imunoperoxidase (IPX) em diluições de até 1:640 (sobrenadante de cultivo) e 1:20.000 (fluído ascítico). Os três AcMs apresentaram um espectro amplo de reatividade, reagindo com antígenos de 14 herpesvírus isolados de doença respiratória ou genital (provavelmente BoHV-1) e com 17 isolados de doença neurológica (supostamente BoHV-5), e apresentaram atividade neutralizante em níveis variáveis contra todos esses isolados. A especificidade protéica dos AcMs não pode ser determinada diretamente, pois nenhum deles reagiu com proteínas virais na técnica de Western blot. Por outro lado, os três AcMs reagiram em IFA com células infectadas com uma cepa do BoHV-5 defectiva nas glicoproteínas E, I e proteína US9, o que exclui estes antígenos como possíveis alvos dos AcMs. Por exclusão (gC, gE, gI) e pela sua forte atividade neutralizante, os AcMs são provavelmente direcionados contra epitopos conservados de outras glicoproteínas do envelope viral que contêm epitopos neutralizantes: a gB e/ou gD. Pelo seu alto título de reação e pelo amplo espectro de reatividade, esses AcMs possuem potencial aplicação em técnicas diagnósticas. Além disso, podem ser úteis para o mapeamento de epitopos neutralizantes conservados nas glicoproteínas do envelope.

ABSTRACTHBx, a small regulatory protein of hepatitis B virus (HBV), augments viral DNA replication by stimulating viral transcription. Among numerous reported HBx-binding proteins, DDB1 has drawn attention, because DDB1 acts as a substrate receptor of the Cul4-DDB1 ubiquitin E3 ligase. Previous work reported that the DDB1-HBx interaction is indispensable for HBx-stimulated viral DNA replication, suggesting that the Cul4-DDB1 ubiquitin E3 ligase might target cellular restriction factors for ubiquitination and proteasomal degradation. To gain further insight into the DDB1-HBx interaction, we generated HBx mutants deficient for DDB1 binding (i.e., R96A, L98A, and G99A) and examined whether they support HBx-stimulated viral DNA replication. In contrast to data from previous reports, our results showed that the HBx mutants deficient for DDB1 binding supported viral DNA replication to nearly wild-type levels, revealing that the DDB1-HBx interaction is largely dispensable for HBx-stimulated viral DNA replication. Instead, we found that DDB1 directly stimulates viral transcription regardless of HBx expression. Through an HBV infection study, importantly, we demonstrated that DDB1 stimulates viral transcription from covalently closed circular DNA, a physiological template for viral transcription. Overall, we concluded that DDB1 stimulates viral transcription via a mechanism that does not involve an interaction with HBx.IMPORTANCEDDB1 constitutes a cullin-based ubiquitin E3 ligase, where DDB1 serves as an adaptor linking the cullin scaffold to the substrate receptor. Previous findings that the DDB1-binding ability of HBx is essential for HBx-stimulated viral DNA replication led to the hypothesis that HBx could downregulate host restriction factors that limit HBV replication through the cullin ubiquitin E3 ligase that requires the DDB1-HBx interaction. Consistent with this hypothesis, recent work identified Smc5/6 as a host restriction factor that is regulated by the viral cullin ubiquitin E3 ligase. In contrast, here we found that the DDB1-HBx interaction is largely dispensable for HBx-stimulated viral DNA replication. Instead, our results clearly showed that DDB1, regardless of HBx expression, enhances viral transcription. Overall, besides its role in the viral cullin ubiquitin E3 ligase, DDB1 itself stimulates viral transcription via HBx-independent mechanisms.

Objetivo: realizar avaliação diagnóstica de condições de vida e saúde dos idosos convivendo em família e comunidade, usuários de uma Unidade Básica de Saúde – UBS e testar o desenvolvimento de uma tecnologia cuidativo-educacional. Metodologia: pesquisa convergente-assistencial, adotando a técnica do grupo de convergência com 13 idosos, que se desenvolveu em sete encontros, em 2013. Resultados: o estudo revelou perspectivas à enfermeira ser facilitadora no desenvolvimento de competências ao autocuidado e estimuladora de idosos para que sejam protagonistas do próprio envelhecimento, instrumentalizada por diretrizes da tecnologia leve de atos de cuidado, fundamentada em referências de enfermagem. Conclusão: o estudo apresentou resultados benéficos aos idosos que se submeteram à experiência e também à enfermagem, pela possibilidade de empreender ações cuidativo-educacionais inovadas.Descritores: Idoso; Tecnologia educacional; Atenção básica; Envelhecimento ativo; Enfermeiro.GROWING THE ELDERLY'S GOOD LIVING AND CARING-EDUCATIONAL TECHNOLOGIES OF NURSING Objective: perform a diagnostic evaluation of living conditions and health of the elderly living in family and community, and users of a Basic Health Unit – UBS, and also test the development of a care-educational technology. Methodology: convergentcare research that adopted the convergence group technique with 13 seniors, which developed during seven meetings in 2013. Results: the paper revealed prospects for the nurse to be a facilitator in the development of self-care skills and stimulate the elderly so that they can be the protagonists of their aging. It was instrumentalized by guidelines of light technology about caring acts based on nursing references. Conclusion: the study presented beneficial results to the elderly who underwent the experience, and also for the nurses, by the possibility of taking innovated caring-educational actions.Descriptors: Elderly; Educational technology; Primary care; Active aging; Nurse.CULTIVO DEL BIENVIVIR DE LOS ANCIANOS Y TECNOLOGÍA CUIDADORA-EDUCACIONAL DE LA ENFERMERÍAObjetivo: realizar una evaluación diagnóstica de las condiciones de vida y salud de los ancianos que conviven en familia, comunidad y son usuarios de una Unidad Básica de Salud – UBS, y testear el desarrollo de una tecnología cuidadora-educacional. Metodología: investigación convergente-asistencial adoptando la técnica del grupo de convergencia perspectivas para que la enfermera sea facilitadora en el desarrollo de competencias para el autocuidado con 13 ancianos, que se desarrolló durante siete encuentros, en el 2013. Resultados: el estudio rebeló y estimuladora de ancianos para que sean protagonistas del propio envejecimiento; instrumentalizada por directrices de la tecnología leve de actos de cuidado y fundamentada en las referencias de enfermería. Conclusion: el estudio presentó resultados benéficos para los ancianos que se sometieron a la experiencia, y también, para la enfermería, por la posibilidad de emprender acciones cuidadoras-educacionales innovadas.Descriptores: Anciano; Tecnologia educacional; Atencion primaria, Envejecimiento activo, Enfermero.

EFEITO DA ADUBAÇÃO SILICATADA NO CULTIVO DO TOMATEIRO SOB ESTRESSE HÍDRICO ALINE MARA CHAVES NUNES¹; ANA JANAINA OLIVEIRA RODRIGUES2; MARCIO PORFIRIO DA SILVA2; GÉSSICA THAÍS DOS SANTOS MOURA2 E KELINE SOUSA ALBUQUERQUE UCHÔA3 1 Engenheiro Agrônoma, Instituto Federal do Ceará – IFCE – campus Limoeiro do Norte, Rua Estevão Remígio, nº 1145, bairro Centro. CEP: 62930-000. Limoeiro do Norte-CE. E-mail: mc_nunes@hotmail.com 2 Mestrando, Departamento de Engenharia Agrícola – Universidade Federal do Ceará – UFC, Av. Mister Hull, s/n - Campus do Pici - CEP 60.021-970 - Fortaleza – CE. E-mail: janainarodrigues22@hotmail.com,marcioporfirioo@gmail.com,gessicathaism@gmail.com 3 Prof. Dr., Bacharelado em agronomia – IFCE – campus Limoeiro do Norte, e-mail: Keline.sousa@ifce.edu 1 RESUMO O uso de silício vem apresentando resultados promissores na agricultura, entretanto, a sua eficácia em minimizar os efeitos do estresse carecem de estudos. Este trabalho teve por objetivo avaliar o efeito da adubação silicatada em híbrido de Tomate cv. Dominador, submetidas a estresse hídrico. O delineamento experimental foi o inteiramente casualizado, com uma testemunha e cinco concentrações de silicato de potássio (0 mL.L-1; 25 mL.L-1; 50 mL.L-1; 75 mL.L-1; e 100 mL.L-1 de K2SiO3) via aplicação foliar, e 10 repetições, as plantas eram irrigadas com base em 60 % da ETo. Os resultados obtidos foram submetidos à análise de variância (F ≤ 0,05), e as médias submetidas ao teste de Tukey (P ≤ 0,05). As variáveis analisadas foram: alturas de plantas (AP); diâmetro do caule (DC); número de folhas (NF) e teor de clorofila (TC). As variáveis DC, NF e TC não divergiram entre os tratamentos. A aplicação de Silicato de Potássio em plantas de tomate apresentou resultado positivo para reduzir o efeito do estresse hídrico no crescimento das plantas. Assim pode-se admitir que este elemento atua de forma benéfica para o desenvolvimento da planta, minimizando os efeitos do estresse. Palavras-chave: irrigação, Lycopersicum esculentum, silício. M. C. NUNES; A. J. O. RODRIGUES; M. P. SILVA; G. T. S. MOURA E S. A. UCHÔA EFFECT OF SILICON FERTILIZING IN TOMATO CULTIVATION UNDER WATER STRESS 2 ABSTRACT The use of silicon has shown promising results in agriculture, however, its effectiveness in minimizing the effects of stress needs to be studied. The objective of this work was to evaluate the effect of silicate fertilization on tomato hybrid cv. Dominator, submitted to water stress. The experimental design was a completely randomized design, with one control and five concentrations of potassium silicate (0 mL.L-1, 25 mL.L-1, 50 mL.L-1, 75 mL.L-1, and 100 mL.L-1 of K2SiO3) via foliar application, and 10 replicates, the plants were irrigated based on 60% of Eto. The results were submitted to analysis of variance (F ≤ 0.05), and the means submitted to the Tukey test (P ≤ 0.05). The analyzed variables were: plant heights (AP); stem diameter (DC); number of leaves (NF) and chlorophyll content (TC). The variables DC, NF and TC did not diverge between treatments. The application of Potassium Silicate in tomato plants presented positive results to reduce the effect of water stress on plant growth. Thus, it can be accepted that this element acts in a beneficial way for the development of the plant and minimizing the effects of stress. Keywords: Irrigation, Lycopersicum esculentum, silicon.

Abstract Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder, yet the genetic cause of up to 50% of cases remains unknown. Here, we show that mutations in KLHL24 cause HCM in humans. Using genome-wide linkage analysis and exome sequencing, we identified homozygous mutations in KLHL24 in two consanguineous families with HCM. Of the 11 young affected adults identified, 3 died suddenly and 1 had a cardiac transplant due to heart failure. KLHL24 is a member of the Kelch-like protein family, which acts as substrate-specific adaptors to Cullin E3 ubiquitin ligases. Endomyocardial and skeletal muscle biopsies from affected individuals of both families demonstrated characteristic alterations, including accumulation of desmin intermediate filaments. Knock-down of the zebrafish homologue klhl24a results in heart defects similar to that described for other HCM-linked genes providing additional support for KLHL24 as a HCM-associated gene. Our findings reveal a crucial role for KLHL24 in cardiac development and function.

ABSTRACTThe rotavirus nonstructural protein NSP1 acts as an antagonist of the host antiviral response by inducing degradation of key proteins required to activate interferon (IFN) production. Protein degradation induced by NSP1 is dependent on the proteasome, and the presence of a RING domain near the N terminus has led to the hypothesis that NSP1 is an E3 ubiquitin ligase. To examine this hypothesis, pulldown assays were performed, followed by mass spectrometry to identify components of the host ubiquitination machinery that associate with NSP1. Multiple components of cullin RING ligases (CRLs), which are essential multisubunit ubiquitination complexes, were identified in association with NSP1. The mass spectrometry was validated in both transfected and infected cells to show that the NSP1 proteins from different strains of rotavirus associated with key components of CRL complexes, most notably the cullin scaffolding proteins Cul3 and Cul1.In vitrobinding assays using purified proteins confirmed that NSP1 specifically interacted with Cul3 and that the N-terminal region of Cul3 was responsible for binding to NSP1. To test if NSP1 used CRL3 to induce degradation of the target protein IRF3 or β-TrCP, Cul3 levels were knocked down using a small interfering RNA (siRNA) approach. Unexpectedly, loss of Cul3 did not rescue IRF3 or β-TrCP from degradation in infected cells. The results indicate that, rather than actively using CRL complexes to induce degradation of target proteins required for IFN production, NSP1 may use cullin-containing complexes to prevent another cellular activity.IMPORTANCEThe ubiquitin-proteasome pathway plays an important regulatory role in numerous cellular functions, and many viruses have evolved mechanisms to exploit or manipulate this pathway to enhance replication and spread. Rotavirus, a major cause of severe gastroenteritis in young children that causes approximately 420,000 deaths worldwide each year, utilizes the ubiquitin-proteasome system to subvert the host innate immune response by inducing the degradation of key components required for the production of interferon (IFN). Here, we show that NSP1 proteins from different rotavirus strains associate with the scaffolding proteins Cul1 and Cul3 of CRL ubiquitin ligase complexes. Nonetheless, knockdown of Cul1 and Cul3 suggests that NSP1 induces the degradation of some target proteins independently of its association with CRL complexes, stressing a need to further investigate the mechanistic details of how NSP1 subverts the host IFN response.

During development, ventricular chamber maturation is a crucial step in the formation of a functionally competent postnatal heart. Defects in this process can lead to left ventricular noncompaction cardiomyopathy and heart failure. However, molecular mechanisms underlying ventricular chamber development remain incompletely understood. Neddylation is a posttranslational modification that attaches ubiquitin-like protein NEDD8 to protein targets via NEDD8-specific E1-E2-E3 enzymes. Here, we report that neddylation is temporally regulated in the heart and plays a key role in cardiac development. Cardiomyocyte-specific knockout of NAE1, a subunit of the E1 neddylation activating enzyme, significantly decreased neddylated proteins in the heart. Mice lacking NAE1 developed myocardial hypoplasia, ventricular noncompaction, and heart failure at late gestation, which led to perinatal lethality. NAE1 deletion resulted in dysregulation of cell cycle-regulatory genes and blockade of cardiomyocyte proliferation in vivo and in vitro, which was accompanied by the accumulation of the Hippo kinases Mst1 and LATS1/2 and the inactivation of the YAP pathway. Furthermore, reactivation of YAP signaling in NAE1-inactivated cardiomyocytes restored cell proliferation, and YAP-deficient hearts displayed a noncompaction phenotype, supporting an important role of Hippo-YAP signaling in NAE1-depleted hearts. Mechanistically, we found that neddylation regulates Mst1 and LATS2 degradation and that Cullin 7, a NEDD8 substrate, acts as the ubiquitin ligase of Mst1 to enable YAP signaling and cardiomyocyte proliferation. Together, these findings demonstrate a role for neddylation in heart development and, more specifically, in the maturation of ventricular chambers and also identify the NEDD8 substrate Cullin 7 as a regulator of Hippo-YAP signaling.

Anticorpos monoclonais (AcMs) produzidos com uma amostra brasileira do herpesvírus bovino tipo 5 (BHV-5) foram utilizados na adaptação e padronização de técnicas rápidas para o diagnóstico de infecções pelo BHV-1 e BHV-5. A detecção de antígenos virais por imunofluorescência em células descamativas (IFCD) foi comparada com o isolamento viral, em secreções nasais de 16 bezerros, sendo 6 inoculados com o BHV-1 e 10 com o BHV-5. De 203 amostras testadas, 182 (89,6%) apresentaram resultados concordantes nos dois testes (143 positivas; 39 negativas). Comparando-se com o isolamento, a IFCD apresentou sensibilidade de 96,6%, especificidade de 70,9%, e precisão de 89,6%. Os AcMs também foram utilizados para detectar antígenos do BHV-5 em impressões frescas do cérebro de bezerros acometidos de enfermidade neurológica e em células de cultivo utilizadas na técnica de soroneutralização (SN), permitindo a obtenção dos resultados em 24 horas. A técnica, denominada de soroneutralização rápida (SNR), apresentou sensibilidade de 97,3%; especificidade de 95,5% e precisão de 96,2% em comparação com a SN tradicional; e sensibilidade de 94,7%, especificidade de 97,3% e precisão de 96,1% em comparação com um ELISA comercial. Esses resultados demonstram que esses AcMs podem ser muito úteis para uso em técnicas rápidas de diagnóstico de infecções suspeitas de BHV-1 ou de BHV-5, sobretudo em situações de surto, quando a tomada de decisões adequadas depende de um diagnóstico rápido e confiável.

A key role of aldosterone and mineralocorticoid receptor is to regulate fluid volume and K+ homeostasis in the body by acting on the renal distal nephron. Global responses of the kidney to elevated aldosterone levels are determined by the coordinate action of different constituent tubule cells, including principal cells, intercalated cells and distal convoluted tubule cells. Recent studies on genetic mutations causing aldosterone overproduction have identified the molecules involved in aldosterone biosynthesis in the adrenal gland, and there is also increasing evidence for mechanisms and signaling pathways regulating the balance between renal NaCl reabsorption and K+ secretion, the two major effects of aldosterone. In particular, recent studies have demonstrated that mineralocorticoid receptor in intercalated cells is selectively regulated by phosphorylation, which prevents ligand binding and activation. Moreover, the ubiquitin ligase complex composed of Kelch-like 3 and Cullin 3 acts downstream of angiotensin II and plasma K+ alterations, regulating Na–Cl cotransporter independently of aldosterone in distal convoluted tubule cells. These and other effects are integrated to produce appropriate kidney responses in a high-aldosterone state, and are implicated in fluid and electrolyte disorders in humans. This review summarizes the current knowledge on mechanisms modulating mineralocorticoid receptor and its downstream effectors in the distal nephron.

The Fbxw7 (F-box/WD repeat–containing protein 7; also called CDC4, Sel10, Ago, and Fbw7) component of the SCF (Skp1/Cullin/F-box protein) E3 ubiquitin ligase complex acts as a tumor suppressor in several tissues and targets multiple transcriptional activators and protooncogenes for ubiquitin-mediated degradation. To understand Fbxw7 function in the murine intestine, in this study, we specifically deleted Fbxw7 in the murine gut using Villin-Cre (Fbxw7ΔG). In wild-type mice, loss of Fbxw7 in the gut altered homeostasis of the intestinal epithelium, resulted in elevated Notch and c-Jun expression, and induced development of adenomas at 9–10 mo of age. In the context of APC (adenomatous polyposis coli) deficiency (ApcMin/+ mice), loss of Fbxw7 accelerated intestinal tumorigenesis and death and promoted accumulation of β-catenin in adenomas at late but not early time points. At early time points, Fbxw7 mutant tumors showed accumulation of the DEK protooncogene. DEK expression promoted cell division and altered splicing of tropomyosin (TPM) RNA, which may also influence cell proliferation. DEK accumulation and altered TPM RNA splicing were also detected in FBXW7 mutant human colorectal tumor tissues. Given their reduced lifespan and increased incidence of intestinal tumors, ApcMin/+Fbxw7ΔG mice may be used for testing carcinogenicity and drug screening.

The transcription factor Nrf2 (NF-E2-related-factor 2) is essential for the oxidative and electrophilic stress responses. Keap1 (Kelch-like-ECH-associated-protein 1), an adaptor for a cullin-3 (Cul3)-based ubiquitin ligase, regulates Nrf2 activity through proteasomal degradation, and acts as a sensor for oxidative and electrophilic stresses. The Keap1-Cul3 complex is a critical regulator of the cellular Nrf2 level, and yet quantitative information regarding their endogenous intracellular concentrations in homeostatic conditions and during stress responses is unknown. We analyzed the absolute amounts of the Nrf2, Keap1, and Cul3 proteins in five murine cell lines by comparison with serial dilutions of purified recombinant protein standards in combination with quantitative immunoblot analyses. In the basal state, the amount of Nrf2 was maintained at lower levels than those of Keap1 and Cul3 proteins, whereas the electrophilic agent diethylmaleate dramatically increased Nrf2 to a level greater than that of Keap1 and Cul3, resulting in the accumulation of Nrf2 in the nucleus. In contrast, Keap1 and Cul3 did not display any changes in their abundance, subcellular localization, or interaction in response to electrophilic stimuli. Our results demonstrate that the regulation of the Nrf2 protein level during stress responses is mediated by the activity but not the composition of the Nrf2-Keap1-Cul3 complex.

Although it is clear that mitochondrial morphogenesis is a complex process involving multiple proteins in eukaryotic cells, little is known about regulatory molecules that modulate mitochondrial network formation. Here, we report the identification of a new yeast mitochondrial morphology gene called MFB1 (YDR219C). MFB1 encodes an F-box protein family member, many of which function in Skp1-Cdc53/Cullin-F-box protein (SCF) ubiquitin ligase complexes. F-box proteins also act in non-SCF complexes whose functions are not well understood. Although cells lacking Mfb1p contain abnormally short mitochondrial tubules, Mfb1p is not essential for known pathways that determine mitochondrial morphology and dynamics. Mfb1p is peripherally associated with the mitochondrial surface. Coimmunoprecipitation assays reveal that Mfb1p interacts with Skp1p in an F-box–dependent manner. However, Mfb1p does not coimmunoprecipitate with Cdc53p. The F-box motif is not essential for Mfb1p-mediated mitochondrial network formation. These observations suggest that Mfb1p acts in a complex lacking Cdc53p required for mitochondrial morphogenesis. During budding, Mfb1p asymmetrically localizes to mother cell mitochondria. By contrast, Skp1p accumulates in the daughter cell cytoplasm. Mfb1p mother cell-specific asymmetry depends on the F-box motif, suggesting that Skp1p down-regulates Mfb1p mitochondrial association in buds. We propose that Mfb1p operates in a novel pathway regulating mitochondrial tubular connectivity.

The DNA damage response (DDR) of a host organism represents an effective antiviral defense that is frequently manipulated and exploited by viruses to promote multiplication. We report here that the large DNA baculoviruses, which require host DDR activation for optimal replication, encode a conserved replication factor, LEF-7, that manipulates the DDR via a novel mechanism. LEF-7 suppresses DDR-induced accumulation of phosphorylated host histone variant H2AX (γ-H2AX), a critical regulator of the DDR. LEF-7 was necessary and sufficient to block γ-H2AX accumulation caused by baculovirus infection or DNA damage induced by means of pharmacological agents. Deletion of LEF-7 from the baculovirus genome allowed γ-H2AX accumulation during virus DNA synthesis and impaired both very late viral gene expression and production of infectious progeny. Thus, LEF-7 is essential for efficient baculovirus replication. We determined that LEF-7 is a nuclear F-box protein that interacts with host S-phase kinase-associated protein 1 (SKP1), suggesting that LEF-7 acts as a substrate recognition component of SKP1/Cullin/F-box (SCF) complexes for targeted protein polyubiquitination. Site-directed mutagenesis demonstrated that LEF-7's N-terminal F-box is necessary for γ-H2AX repression andAutographa californicamultiple nucleopolyhedrovirus (AcMNPV) replication events. We concluded that LEF-7 expedites virus replication most likely by selective manipulation of one or more host factors regulating the DDR, including γ-H2AX. Thus, our findings indicate that baculoviruses utilize a unique strategy among viruses for hijacking the host DDR by using a newly recognized F-box protein.

Endothelial dysfunction is an important risk factor for cardiovascular disease, and it represents the initial step in the pathogenesis of atherosclerosis. Failure to protect against oxidative stress-induced cellular damage accounts for endothelial dysfunction in the majority of pathophysiological conditions. Numerous antioxidant pathways are involved in cellular redox homeostasis, among which the nuclear factor-E2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)–antioxidant response element (ARE) signaling pathway is perhaps the most prominent. Nrf2, a transcription factor with a high sensitivity to oxidative stress, binds to AREs in the nucleus and promotes the transcription of a wide variety of antioxidant genes. Nrf2 is located in the cytoskeleton, adjacent to Keap1. Keap1 acts as an adapter for cullin 3/ring-box 1-mediated ubiquitination and degradation of Nrf2, which decreases the activity of Nrf2 under physiological conditions. Oxidative stress causes Nrf2 to dissociate from Keap1 and to subsequently translocate into the nucleus, which results in its binding to ARE and the transcription of downstream target genes. Experimental evidence has established that Nrf2-driven free radical detoxification pathways are important endogenous homeostatic mechanisms that are associated with vasoprotection in the setting of aging, atherosclerosis, hypertension, ischemia, and cardiovascular diseases. The aim of the present review is to briefly summarize the mechanisms that regulate the Nrf2/Keap1–ARE signaling pathway and the latest advances in understanding how Nrf2 protects against oxidative stress-induced endothelial injuries. Further studies regarding the precise mechanisms by which Nrf2-regulated endothelial protection occurs are necessary for determining whether Nrf2 can serve as a therapeutic target in the treatment of cardiovascular diseases.

Qu’ont en commun l’art spiritualiste de Hector de Saint-Denys Garneau et le monisme de Paul-Émile Borduas ? Premier poète québécois à faire de la peinture un objet de réflexion esthétique, Saint-Denys Garneau tient pourtant en suspicion la modernité artistique, refusant « l’injure à l’art » que représentent pour lui le cubisme et l’art abstrait. Si l’ekphrasis, chez Saint-Denys Garneau, s’éloigne du « pittoresque » pour s’approcher du « pictural », l’idéalisation du sujet et l’objectivation de la vision qu’il cultive diffèrent cependant fortement de la conception du tableau de Borduas. Aux notions d’ordre, de centre, d’harmonie, d’unité, de transparence et d’élévation autour desquelles le poète et artiste ordonne encore le visible, Borduas oppose celles d’automatisme psychique, d’écriture automatique, de liberté du geste, de « désir-passion », de « grâce surrationnelle », appelant une exploration du chaos du monde intérieur et une plongée dans l’inconscient menant inéluctablement à un contact brutal avec la matière sensible. Prenant acte de l’apparition de Garneau et Borduas au même moment sur la scène publique montréalaise, vers 1937-1938, et cherchant à mesurer le pouvoir de séduction particulier qu’exercent sur eux durant ces années décisives la pensée et l’oeuvre de John Lyman, l’auteur interroge la conception antagoniste que chacun se forge du dessin et de la couleur et examine certains des enjeux essentiels, après la publication du Journal de Saint-Denys Garneau, qui déterminent la posture double et ambiguë de Borduas à l’endroit de l’héritage de l’écrivain.

Thalidomide and its derivatives (lenalidomide, pomalidomide, avadomide, iberdomide hydrochoride, CC-885 and CC-90009) form the family of immunomodulatory drugs (IMiDs). Lenalidomide (CC5013, Revlimid®) was approved by the US FDA and the EMA for the treatment of multiple myeloma (MM) patients, low or intermediate-1 risk transfusion-dependent myelodysplastic syndrome (MDS) with chromosome 5q deletion [del(5q)] and relapsed and/or refractory mantle cell lymphoma following bortezomib. Lenalidomide has also been studied in clinical trials and has shown promising activity in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). Lenalidomide has anti-inflammatory effects and inhibits angiogenesis. Pomalidomide (CC4047, Imnovid® [EU], Pomalyst® [USA]) was approved for advanced MM insensitive to bortezomib and lenalidomide. Other IMiDs are in phases 1 and 2 of clinical trials. Cereblon (CRBN) seems to have an important role in IMiDs action in both lymphoid and myeloid hematological malignancies. Cereblon acts as the substrate receptor of a cullin-4 really interesting new gene (RING) E3 ubiquitin ligase CRL4CRBN. This E3 ubiquitin ligase in the absence of lenalidomide ubiquitinates CRBN itself and the other components of CRL4CRBN complex. Presence of lenalidomide changes specificity of CRL4CRBN which ubiquitinates two transcription factors, IKZF1 (Ikaros) and IKZF3 (Aiolos), and casein kinase 1α (CK1α) and marks them for degradation in proteasomes. Both these transcription factors (IKZF1 and IKZF3) stimulate proliferation of MM cells and inhibit T cells. Low CRBN level was connected with insensitivity of MM cells to lenalidomide. Lenalidomide decreases expression of protein argonaute-2, which binds to cereblon. Argonaute-2 seems to be an important drug target against IMiDs resistance in MM cells. Lenalidomide decreases also basigin and monocarboxylate transporter 1 in MM cells. MM cells with low expression of Ikaros, Aiolos and basigin are more sensitive to lenalidomide treatment. The CK1α gene (CSNK1A1) is located on 5q32 in commonly deleted region (CDR) in del(5q) MDS. Inhibition of CK1α sensitizes del(5q) MDS cells to lenalidomide. CK1α mediates also survival of malignant plasma cells in MM. Though, inhibition of CK1α is a potential novel therapy not only in del(5q) MDS but also in MM. High level of full length CRBN mRNA in mononuclear cells of bone marrow and of peripheral blood seems to be necessary for successful therapy of del(5q) MDS with lenalidomide. While transfusion independence (TI) after lenalidomide treatment is more than 60% in MDS patients with del(5q), only 25% TI and substantially shorter duration of response with occurrence of neutropenia and thrombocytopenia were achieved in lower risk MDS patients with normal karyotype treated with lenalidomide. Shortage of the biomarkers for lenalidomide response in these MDS patients is the main problem up to now.

Abstract Introduction: Bay 61-3606 is a cell-permeable imidazopyrimidine compound that acts as a potent, ATP-competitive, reversible, and highly selective inhibitor of Syk tyrosine kinase activity with no inhibitory effect against Btk, Fyn, Itk, Lyn, and Src. BAY 61-3606 has been also shown to inhibit Syk-mediated cellular functions such as glucose-tyrosine phosphorylation of I κ B α and p65 nuclear translocation. It further exhibits a good oral bioavailability and in vivo efficacy in rat models. Recently, Bay 61-3606 was found to inhibit cell proliferation and SDF-1a-induced migration of MM cells (1). Based on these promising preliminary data we further investigated the potential of Bay 61-3606 as new anti-MM agent. Methods and Results: Bay 61-3606, at concentrations as low as 10 nM, induced significant (p<0.01) inhibition of cell growth in MM cells (MM.1S, H929 and RPMI-8266) as shown by WST-1 cell proliferation assay. The inhibition of proliferation was accompanied by increased cell cycle arrest at G0/G1 (from 60% to 75%). More importantly, Bay 61-3606 dose dependently induced MM cells apoptosis suggesting that Bay 61-3606 has potent anti-MM properties. Since Bay 61-3606 was originally reported as a SYK inhibitor, we analyzed whether the effects of Bay 61-3606 were due to SYK inhibition. For this purpose, we first checked the expression of SYK in all the MM cell lines (MM.1S, H929, U266, OPM2 and RPMI-8226). And to our surprise, although all these cells were sensitive to Bay 61-3606 treatment, several of these cell lines (H929, U266 and RPMI-8226) had no detectable SYK expression by Western Blot assay. This suggests that the anti-MM effects of Bay 61-3606 are not mediated by SYK inhibition, which was further confirmed by using another specific SYK inhibitor GS-9973. Further mechanistic studies showed that Bay 61-3606 significantly downregulated protein levels of IKZF1, IKZF3, c-MYC and IRF-4 in IMiD®-sensitive and resistant MM cell lines (MM.1S, H929 and RPMI-8266) by Western Blot assay. In contrast, real-time PCR assay indicated IKZF1/3-mRNA level was not altered, suggesting that Bay 61-3606 regulates IKZF1/3 at post-translational level. The proteinase inhibitor MG132 and cullin-dependent ubiquitin ligase inhibitor MLN4924 blocked the downregulation IKZF1/3 by Bay 61-3606 confirming that Bay 61-3606 induced IKZF1/3 protein degradation. Consistent with its proapoptotic effects, Bay 61-3606 downregulated MDM2 phosphorylation, upregulated P53 level and induced PARP cleavage as confirmed by Western Blot assy. Conclusion: In summary, our results demonstrate that Bay 61-3606 has anti-MM effects by inducing cell cycle arrest and apoptosis, and this effect is independent of SYK inhibition. Similar to IMiD® compounds, Bay 61-3606 induces IKZF1 and IKZF3 protein degradation in MM cells. More importantly, Bay 61-3606 has effects on both IMiD®-sensitive and resistant myeloma cells and may represent a novel potent anti-MM agent. References: (1). Koerber RM, et al. Exp Hematol Oncol. 2015. Disclosures Lentzsch: BMS: Consultancy; Foundation One: Consultancy; Celgene: Consultancy, Honoraria.

USOS Y ABUSO DE LOS RECURSOS HÍDRICOS POR DENDEICULTURA EN LA AMAZONÍA PARAENSEUSES AND ABUSES ON THE HYDRIC RESOURCES BY THE OIL PALM CULTIVATION IN THE PARÁ’S AMAZONRESUMONo texto sustenta-se que a dendeicultura atua como agrohidronegócio na Amazônia paraense. Enquanto produção do espaço do capital, ela usufrui de recursos hídricos a partir da apropriação da terra, confundindo direito de propriedade com direito à propriedade. Por agrohidronegócio compreende-se uma categoria analítica das tensões, disputas e conflitos territoriais decorrentes da ação do capital para usar e se apropriar dos corpos hídricos no espaço. Entende-se por dendeicultura as determinações espaciais que possibilitam o cultivo do dendezeiro nesta fração da Amazônia e por meio destas reorganizar a paisagem, a configuração espacial e a dinâmica social dos lugares sob sua influência. Mostra-se que a necessidade imperativa de água explica a distribuição dos dendezais nas sub-bacias hidrográficas da microrregião de Tomé-açu, ocasionando impactos ambientais. Por isso cria-se uma representação espacial que oculta tais impactos, nem mesmo a captação de água. Na literatura a água não aparece para esse agrohidronegócio como insumo na composição dos custos da produção de óleos de dendê e nenhuma empresa é cobrada pelo direito de uso. O direito de outorga para captar água parece suficiente para dizer que estão cumpridas as determinações da política nacional de recursos hídricos. Está-se diante de prática que produz uma representação de espaço onde esse vetor econômico silencia suas responsabilidades, impactos e riscos ambientais e se apresenta como recuperador de áreas degradadas econômica e ambientalmente, gerador de empregos, renda e inclusão social. Palavras-chave: Dendê; Rural; Outorgas; Água; Apropriação.ABSTRACTIt is argued that oil palm cultivation acts as an hydroagricultural business in the Pará’s Amazon. As production of the capital space, it takes advantage of water resources based on the appropriation of land, confusing the right of property with the right to property. Hydroagricultural business is an analytical category of tensions, disputes and territorial conflicts resulting from the action of capital to use and appropriate water bodies in space. Oil palm cultivation is understood as the spatial determinations that make it possible to cultivate oil palm in this part of the Amazon and, through these, reorganize the landscape, the spatial configuration and the social dynamics of the places under its influence. It is shown that the imperative need for water explains the distribution of oil palm in the hydrographic sub-basins of the micro-region of Tomé-açu causing environmental impacts. That is why a spatial representation is created that hides such impacts, not even the water catchment. In the literature, water does not appear to this hydroagricultural business as an input in the composition of the costs of producing palm oil and no company pays for the right to use it. The granting right to collect water seems sufficient to say that the determinations of the national water resources policy are being fulfilled. It is a practice that produces a representation of space where this economic vector silences its responsibilities, impacts and environmental risks and presents itself as a recuperated of degraded areas economically and environmentally, generating jobs and social inclusion.Keywords: Oil Palm; Rural; Grants; Water; Appropriation.RESUMENEl texto argumenta que la dendeicultura actúa como agrohidronegócio en la Amazonía paraense. Mientras produce el espacio de lo capital, disfruta de los recursos hídricos de la apropiación de la tierra, confundiendo los derechos de propiedad con el derecho a la propiedad. Agrohidonegocío es una categoría analítica de tensiones, disputas y conflictos territoriales derivados de la acción del capital para utilizar y cuerpos de agua apropiados en el espacio. La dendeicultura se entiende como las determinaciones espaciales que permiten el cultivo de palma aceitera en esta fracción de la Amazonía y a través de estos reorganizar el paisaje, la configuración espacial y la dinámica social de los lugares bajo su influencia. Se demuestra que la necesidad imperiosa de agua explica la distribución de palmas de aceite en las subcuencas hidrográficas de la microrregión de Tomé-açu, causando impactos ambientales. Por lo tanto, se crea una representación espacial que oculta tales impactos, ni siquiera la captura de agua. En la literatura el agua no aparece para este agrohidronegócio como insumo en la composición de los costos de la producción de aceites de palma y no se cobra a ninguna empresa por el derecho de uso. El derecho de concesión a capturar el agua parece suficiente para decir que se cumplen las determinaciones de la política nacional de recursos hídricos. Se enfrenta a una práctica que produce una representación del espacio donde este vector económico silencia sus responsabilidades, impactos y riesgos ambientales y se presenta como una recuperación de áreas económica y ambientalmente degradadas, generando empleos, ingresos e inclusión social.Palabras clave: Palma Aceitera; Rural; Subvenciones; Agua; Apropiación.

Resumen En el cuadro “La primera chacra”, a través de una paleta vibrante de colores contrastantes y delicados trazos sobre un fondo monocromático oscuro, Yahuarcani representa el lugar donde las plantas son cultivadas, un espacio lleno de vida y espíritus. Según el conocimiento Amazónico, las plantas tienen distintos espíritus que pueden influenciar el mundo material y los cuerpos humanos, y pueden comunicarse con la gente. Esta perspectiva de la naturaleza cuestiona el punto de vista moderno occidental sobre el cultivo de plantas y el lugar de ellas en la sociedad. Pero “La primera chacra” no es una representación del entorno natural, ni una descripción visual de temas mitológicos. Por el contrario, Yahuarcani pinta un concepto más abstracto: una fuerza natural, productora de vida, un dominio donde lo espiritual y lo material están interconectados. En “La primera chacra”, así como en las pinturas “El río” o “Al caer la noche”, el entorno Amazónico no es explícito. Yahuarcani se inspira en el conocimiento y mitos de la Amazonía para producir un trabajo evocativo sobre ella. A través de pinturas en las que el tratamiento estético de las imágenes predomina sobre la narrativa, Yahuarcani da nueva forma al conocimiento ancestral amazónico, reivindicando su importancia y validez en el mundo contemporáneo. Abstract In the first painting “La primera chacra” (The First Little Farm), through a very vibrant palette of contrasting colors and delicate traces over a monochrome dark background, Yahuarcani depicts the place where plants are cultivated, a space full of life and of spirits. According to the Amazonian knowledge, plants have distinct spirits that are able to influence the material world and human bodies, and can communicate with people. This perspective on nature questions modern Western views on farming and the place of plants in society. But “The First Little Farm” is not a depiction of the natural environment, neither a visual description of mythological subjects. Rather, Yahuarcani paints a more abstract concept of it: a natural force, producer of life, a domain where the spiritual and the material are interconnected. In “The First Little Farm” as well as the paintings El río (River) or Al caer la noche (Nightfall), the Amazonian environment is not explicit. Yahuarcani is inspired by the knowledge and myths of the Amazon to produce a work evocative of the Amazonia in his own language. Through paintings in which the aesthetic treatment of the images predominates over the narrative, Yahuarcani reshape the ancient Amazonian knowledge, reassessing his importance and validity in the contemporary world. ReferencesBorea, Giuliana. “Personal cartographies of a Huitoto mythology: Rember Yahuarcani and the enlarging of the Peruvian contemporary art scene.” Revista de Antropologia Social dos Alunos do PPGAS-UFSCar 2, n. 2 (Jul.-Dec. 2010): 67-87.Yahuarcani, Rember. “Los ríos de nuestra memoria.” Mundo Amazónico 5 (2014): 197-209.Yllia Miranda, María Eugenia. “Antropófagos contemporáneos: paradojas y lógicas visuales en la pintura amazónica contemporánea peruana.” Actas del Seminario Internacional Estudios y Encuentros entre Antropología y Arte. Lima: PUCP, en prensa.

(francuski) Plusieurs sources historiques nous sont parvenues qui attestent le r?le actif des cultes de saint Simeon et saint Sava, les premiers saints de l'Eglise Serbe. Tout en ?tant compl?mentaires, ces deux cultes diff?rent par leur fonction, notamment du fait que saint Simeon, fondateur de l'Etat et de la dynastie serbes, est c?l?br? comme un saint myroblite, alors que saint Sava, premier archev?que de l'Eglise serbe ind?pendante, est v?n?r? comme un saint thaumaturge. Leur fusion en un culte faisant l'objet d'une c?l?bration unique a eu lieu ? l'?poque du roi Milutin (1282-1321). Le pr?sent article ?tablit que la formation finale du nouveau programme monarchique de Milutin, probablement inspir? par la communaut? monastique de Chilandar, se situe entre 1314-1316 et 1321. Outre l'observation g?n?rale de la fonction de ce culte et de sa polys?mie, nous proc?dons ?galement ? une analyse du ph?nom?ne constitu? par les pri?res de saint Sim?on et saint Sava apparaissant dans les chartes de l'?poque du roi Milutin ? indice certain de l'efficacit? reconnue du nouveau culte ? et de ses implications politiques. Cependant, une image compl?te de la signification des pri?res de ces deux saints dans les chartes et de leur usage dans le domaine id?ologique, ne peut ?tre obtenue qu'en proc?dant ? une analyse des divers types de t?moignages ? chartes, fresques, offices, canons et apologies ? c?l?brant ces deux personnages. La plus ancienne repr?sentation conserv?e de ces deux saints sur des peintures murales se trouve dans l'?glise Saint-Nic?tas pr?s de Skoplje. Les portraits associ?s de saint Simeon et saint Sa va situ?s sur le mur nord du naos de l'?glise datent de la deuxi?me d?cennie du XIV?me si?cle (avant 1316). Leur ex?cution pouvant ?tre situ?e apr?s la conclusion d'une paix ayant mis fin ? des conflits int?rieurs. Au tout d?but, le motif ?des pri?res de saint Sim?on et saint Sa va? a en fait trouv? place dans les clauses p?nales des chartes de l'?poque. Le r?le de la pri?re y est d'assurer une protection ancestrale et sacrale aux dons pieux du souverain actuel. Sur un plan plus large, ces pri?res visent ?galement ? assurer une protection c?leste aux conqu?tes du roi et aux garanties formul?es dans les documents de donation, mais aussi la protection de la patrie dont la prosp?rit? est fond? sur la fonction sot?riologique rendue possible par les pri?res des saints protecteurs. La premi?re mention d'une telle invocation invitant les deux saints serbes ? anath?matiser celui qui violerait les dispositions de l'auteur d'une charte, appara?t dans une charte de confirmation d?livr?e par Milutin au monast?re de Chilandar au sujet de la donation d'une cellule de Sainte-Parasc?ve sise au village de Tmorani pr?s de Skopje (1299/1300 : Chil. si., n. 9, 1. 67). Les pri?res des deux saints dans leur fonction de protecteurs de l'Etat et de la dynastie apparaissent ?galement dans d'autres documents de souverains datant du d?but du XIV?me si?cle. La mention de Vladislav, cousin du roi Milutin, au nombre d'h?ritiers potentiels dans les clauses p?nales d'une charte du roi Milutin d?livr?e au monast?re de Chilandar (Chil. si., n. 11), rend possible une nouvelle datation, plus pr?cise, de ce document entre 1314 et 1316. Cette charte nous fournit donc un cadre chronologique pour l'?tablissement des pri?res des deux saints serbes, lequel cadre co?ncide avec l'apparition de leur repr?sentation associ?e sur les peintures du monast?re Saint-Nicolas dans la r?gion de Skoplje, que le roi a offert ? Chilandar, par le biais de la charte mentionn?e. A cette ?poque-l?, au cours des deux premi?res d?cennies du XIV?me si?cle, le moine Tedosije, inspir? par la communaut? monastique de Chilandar, fut charg? de proc?der, selon les go?ts litt?raires et les besoins id?ologiques de l'?poque, ? une r?daction monumentale de la litt?rature hagiographique jusqu'alors cr??e, et de jeter les fondements du nouveau culte des premiers saints nationaux comme principal vecteur de l'id?e d'origine charismatique de la dynastie. La synth?se ainsi obtenue vers les ann?es vingt du XVI?me si?cle r?unit les exploits spirituels et les r?sultats des efforts convergents d'une ?lite rattach?e tant ? la cour de Serbie qu'au centre religieux de Chilandar. La co?ncidence d?j? relev?e entre les chartes, la peinture murale et l'apparition d'un nouveau culte s'inscrivant dans un programme politique plus vaste, avec sa c?l?bration en litt?rature, ne saurait ?tre fortuite. L'approche du centenaire du royaume repr?senta, sans doute, un moment crucial pour placer les saints nationaux au centre d'un complexe de programmes sot?riologiques, d?j? effectif au moment o? l'Etat serbe s'est activement tourn? vers l'Orient orthodoxe. L'unit? fondamentale et fonctionnelle du nouveau culte se manifeste par des actes miraculeux s'inscrivant dans un cadre clairement ?tabli, d?fini dans le sens spatial et national, et refl?tant un type de saintet? ?galement pr?sent chez les autres peuples du Moyen Age. La phase de repr?sentation de la dynastie devant le Christ est remplac?e par une signification plus vaste et sot?riologique de la repr?sentation de l'Etat, induite par les pri?res des deux saints. Ceci a entre autre abouti ? la symbolique polys?mique de Chilandar comme ? le nouveau Sion ?. La mention de saint Simeon et saint Sava dans les chartes de Milutin, publi?es durant les derni?res ann?es de sa r?gence, appara?t ?galement dans les documents de l'empereur Dusan (1331-1355). Cette reprise s'inscrit probablement comme un ?l?ment du concept complexe faisant du roi Milutin un exemple de la nouvelle fa?on de r?gner, lequel concept ?tait li? aux plans entrant dans la politique ext?rieure de l'empereur Dusan ? ? savoir une offensive sur les contr?es orientales de l'Empire grec ? pr?sent?e comme une poursuite des conqu?tes du roi Milutin. Etant les saints les plus importants de l'id?ologie monarchique serbe, Simeon et Sava seront c?l?br?s m?me apr?s la chute de l'Empire (1371). Ils sont peints comme un couple de saints, ou plac?s comme deux pendants, c?l?br?s comme ? les deux saints ? dans les chants. Ils sont devenus, ? travers leurs cultes r?unis, le fondement de l'id?ologie de l'Etat et de l'Eglise au cours de l'histoire serbe ult?rieure. .

Abstract Background: IMiDs cytotoxicity in MM cells is mediated through their binding to CRBN within the cullin ring (CRL4) ligase. This binding triggers the ubiquitylation and proteasomal degradation of IKZF1/3. CRBN thalidmomide binding domain (TBD) was mapped to its C-terminus and the crystal structure of the CRBN-IMiDs bound complex identified several aa within exons 10 and 11 as essential for the IMiDs glutarimide ring binding to CRBN. Several groups including ours have reported that loss of CRBN is associated with resistance to IMiDs, however this does not appear to be the sole mechanism of resistance in primary MM cells. Furthermore, and while CRBN mutants (Y384A and W386A) are defective for IMiDs binding, acquisition of CRBN mutation is a rare event in MM patients suggesting alternative mechanisms of resistance. Thirteen splice variants of CRBN are reported (ensembl.org), however to date it is unclear whether these isoforms are expressed as proteins and their contribution to IMiDs resistance is yet to be defined. Methods and Results: In this study we investigated whether expression of full length CRBN (FL-CRBN) relative to its variants lacking the TBD and particularly the splice variant CRBN-005 (ENST00000424814) lacking exon 10, contribute to IMiDs resistance. RNA-seq analysis was performed on CD138 sorted cells in 15 paired patients samples obtained sequentially prior to lenalidomide treatment initiation and after development of resistance. Transcriptome sequence data was generated by RNA-seq with a minimum of 70x106 reads per sample. Filtered Fastq files were processed with the splice aligner TopHat against hg19. Of interest, splice isoforms of CRBN including isoforms lacking exon 10 and to a lesser extent exon 8 were identified in nearly all patients, albeit with at variable frequency. Splicing almost universally involved the full length of exon 10 including aa W382 and H378 that are now recognized to bind the 2 carbonyls residues on the IMiDs glutarimide ring and hence required for IMiDs binding to CRBN. Of note, mutation analysis of these 30 samples using the GATK RNAseq pipeline did not identify any mutations within CRBN exons 10 or 11. Furthermore, exome sequencing of CD138 cells from 10 additional lenalidomide resistant patients did not identify any CRBN SNVs or indels confirming the rarity of this event. In order to assess the contribution of FL-CRBN transcript and/or its splice variant (CRBN-005) to IMiDs sensitivity, we first confirmed by qRT-PCR (n=26, amplicons with 2 sets of primers overlapping exons 8-9 and exons 10-11) that low pre-treatment CRBN levels was significantly associated with shorter PFS (p=0.008) to lenalidomide. We next compared FL-CRBN (probe spanning exons 10-11) and CRBN-005 (Taqman probe spanning exons 9-11 junction) mRNA expression (qRT-PCR) in paired samples (n=21 patients - 42 pairs) collected immediately pre-treatment and at the time of progression post-lenalidomide. In 9/21 (42.8%), a significant reduction (2-ΔΔCT < 0.75) in the FL-CRBN amplicon levels was observed between the paired pre- and post-treatment samples. The ratio of spliced CRBN-005 to full length CRBN (CRBN-005 / FL-CRBN) was significantly higher (1.3 to 54 fold) at the time of relapse in 11/21 (52.3%), including 5 patients where CRBN-FL transcript levels were unchanged. Lastly, to confirm whether CRBN-005 expresses a stable protein and to evaluate its role in IMiDs resistance, we cloned spliced CRBN-005 isoform (Δ10-CRBN) or full length CRBN (WT-CRBN) into pcDNA3 plasmid and transfected them in HEK293T cells. The Δ10-CRBN and WT-CRBN plasmids expressed a ~ 45 and 51 kDa proteins respectively that were detectable by western blotting with CRBN65 antibody (Celgene). Functionally, we co-transfected HEK293T cells with a lentiviral plasmid expressing Aiolos and the Δ10-CRBN or WT-CRBN plasmids. While treatment of WT-CRBN expressing cells with lenalidomide resulted in full loss of Aiolos, the expression of Δ10-CRBN significantly mitigated this effect. Conclusions: Study of the transcriptome of paired pre- and post-IMIDs in myeloma primary cells confirms the expression of CRBN-005 splice isoform lacking the IMiDs binding domain and reveals its enrichment in a subset of IMiDs resistance patients. Functionally we have demonstrated a novel mechanism of IMiDs resistance where the spliced isoform CRBN-005 acts as a dominant negative blocking IMiDs binding the CRL4 E3 ligase. Disclosures Bahlis: Celgene: Honoraria, Research Funding.

Acciones y reacciones reversibles entre organismo y ambiente crean un proceso permanente adaptativo que conduce a la aclimatación. En realidad la adaptación es una forma de Mal de Altura cuya curación es la aclimatación. Se trata pues de una noxa climática que actúa sobre el individuo y la raza a punto tal que ha quedado enjuiciado en los relatos, documentos y libros de los comentarios o Historiadores del Tahuantisuyo y la Colonia, La "agresión climática" aparece definida por la acción nociva del "temple" andino para los costeños y del 'temple" costeño para los serranos. Tal factor fué contemplado en la Legislación social del Incario y Pachacutec y otros Incas la utilizaron en la táctica de la guerra (Garcilaso ). Se dejó sentir visiblemente la "agresión climática" en la reproducción humana y animal, Sobre lo primero el milagro de San Nicolás de Tolentino referente al primer hijo de padres españoles logrado en Potosí, tiene todas las características de un tan sensacional acontecimiento que entró en la tradición de la Villa hasta que la Escuela Médica Peruana encontró su explicación biológica, demostrando que, en la altura, a la fertilidad se llegó mediante un proceso lento de aclimatación progresiva de las razas españolas en los elevados altiplanos de Sud-américa. Análogo hecho se recoge del Acta de la Fundación de Lima y al mismo se refiere insistentemente el Padre Cobo. También aparecen informaciones precisas sobre la preocupación genética de las sociedades autóctonas del Tahuantisuyo al prohibirse el matrimonio entre hermanos contra lo admitido generalmente, pues sólo fué a partir del gobierno de Tupac Yupanqui, que se autorizó tal cosa y únicamente para sujetos de sangre real. Es interesante anotar que sobre el mestizaje indo-hispánico estableciera el Padre Cobo conclusiones genéticas que pueden estimarse como anticipaciones mendelianas. Queremos dejar claramente establecido que la adaptación, y la aclimatación de raza en la altura constituye un hecho perfectamente establecido como lo demuestra la descendencia hispánica en los Andes,. La regla en la aclimatación es la fertilidad. Si al atletismo se obtiene creando un déficit de oxígeno por encima del requerimiento normal; el déficit de oxígeno permanente de la altitud debe conducir necesariamente al atletismo. Luego el acostumbramiento a la fatiga debe ser la ley orgánica de altura. Pues bien todos los Cronistas están conformes en hablamos de la extraordinaria resistencia física del andino y como el cultivo del esfuerzo se incorporó profundamentalmente en su vida diaria -ciudades y viviendas en las cumbres; en su organización social, chasquis y cargadores del Inca; en las distintas formas del culto-apachetas; en la selección de la nobleza, fiesta del Huaracu, orden de los "orejones" y en fin en las ceremonias nupciales, fiestas del Atacaimita y Paltay - En todas ellas el entrenamiento en lo que respecta a concentración, alimentación y ejercicios atléticos y vida rigurosamente higiénica era análogo a lo que ocurrió en los juegos olímpicos de Grecia y en la preparación actual de las Olimpiadas. La raza autóctona estuvo tan hondamente impregnada del ambiente telúrico que en la constitución de las sociedades tenía que actuar, imperativamente, un determinismo bio-climático. Así se explica el sentido de las migraciones a localidades del mismo temple y el nomadismo de retorno de la organización de los Mitimaes, lo que trajo como consecuencia un cruzamiento incesante que daba homogeneidad a la raza, cuidando siempre de la estabilidad del clima de altura. La Sociología incaica pues fué bio-climática; la influencia biológica del altiplano se dejó sentir en el hombre, la raza y las sociedades de América en la paz, en la guerra y en la colonización. La Corona de España conoció el hecho y trató de fomentarlo con una abundantísima legislación que sólo quedó escrita. La República ignora este problema. En las guerras de emancipación toda vez que las tropas porteñas combatieron en localidades de escasa elevación, como ocurrió en las proximidades de Jujuy (1236 m. sobre el nivel del mar), Salta (1185 m.) y Tucumán (477 m.) salieron vencedoras, mientras que fueron derrotadas por los ejércitos andinos en el Alto Perú, por encima de 3000 m. de altitud, Sipe-sipe, Ahoyuma y Huaqui. San Martín se negó a atravesar el altiplano como si tuviera la intuición biológica de la agresión climática que históricamente venció a los hombres del Llano. El Instituto Nacional de Biología Andina hace un llamamiento para que los pueblos indo-hispánicos reciban de los poderes del Estado la protección que su biología reclama y que el problema de la vida y de las sociedades andinas que con tanta devoción lo está resolviendo la Universidad de San Marcos reciba todo el apoyo que la Nación debe darle.

Background. The children’s opera in all its diversity has undergone a rapid path to its formation and development, responding to changes in the art and aesthetic space of musical culture. The active being and the practical use of this phenomenon only emphasize the gaps in musicology science more acutely. Some researchers combine with the notion of «children’s opera» both works that involve children to participate in the performing process, and those which are aimed at a certain age audience. Other authors put the term «opera for children» as universal, but use it to describe various works. However, if the information about this genre is contained in the scientifi c literature, research on opera for children-performers analogue, children’s operetta which was formed and used by considerable demand in the late 19th – in the fi rst half of the 20th century in the English-speaking countries, is practically absent. This determines the relevance of the chosen subject. Objectives. The objective of this study is to consider the features of the libretto, the compositional and dramaturgical properties of the children’s operetta by J. L. Gaynor The House that Jack Built as one of the English-language samples of the genre. Methods. So far these methods were been applied: historical, structural and functional, comparative. Results. It is diffi cult to indicate the exact date of the children’s operetta emergence. It is known from available literature that it became widespread in the 1880s. In the following decades, the popularity of children’s operettas does not fade, rather, it only grows. The school authorities even were worried about such an intensity of extracurricular work. However, this fact did not affect the number of performances. There are books containing instructions and guidance, tips on probable diffi culties that could be faced by fi rst-time directors. In particular, it was recommended to divide responsibilities between school departments and draw up a general plan of action. Attention was paid to organizing an advertising campaign to attract as many viewers as possible. With such performance enthusiasm, there was a certain lack of repertoire written specifi cally for children and adolescents. Not surprisingly, the music teachers sought to replenish it. Among them was an American piano and harmony teacher Jessie Lovel Smith Gaynor (1863–1921) who composed The House that Jack Built (1902). This is not the only sample of children’s operetta in the heritage of J. L. Gaynor, she wrote a few more works, mostly after fairy tales: The Lost Princess Bo-Peep (its plot matches Jack’s one), The Toy Shop, Snow White, The Magic Wheel, Three Wishes, The Return of Proserpina, and On Plymouth Rock. The libretto of The House that Jack Built, written by A. G. D. Riley, is compiled on the basis of nursery rhymes, which are an integral part of the English-speaking countries culture. The operetta includes 24 folklore texts (full or fragmented): poems, two counters, and a ballad. To organize the plot, the librettist used the «stringing» method, or the cumulative principle, joining each subsequent element to the previous one with the help of the Mother Goose’s recitative lines. She is the key character, who greets and introduces new guests at her party. This principle is refl ected in the organization of the whole operetta. Mother Gooses’ cues are a refrain similar to the poem The House that Jack Built. Each character is not related to the previous one or the next, they are united only by belonging to the images of folk poetry. Since the libretto is mainly based on miniatures (with one or two verses), there are many participants of the performance: 43 characters, 21 thrushes, and collective characters, the number of which is not specifi ed precisely. There is no plot in common sense – as a series of related events built in accordance with certain principles – in The House that Jack Built. Rather, it reminds the carnival procession, in which characters are appearing one by one. They have bright, sometimes extravagant costumes, which vary with the speed of the pattern in the kaleidoscope. The structure of the operetta is simple and clear. It consists of two acts, divided into 19 big numbers (9 in the fi rst action, 10 in the second), which are often built in the form of a suite. The balance among solo-ensemble and choral numbers in The House that Jack Built is unequal. The choruses prevail in the operetta (there are about 20 of them). It is diffi cult to name the exact number because the author does not always clarify the exact cast. Solo and ensemble numbers are 4 times fewer; in addition, there are 2 numbers in the 2d act, in which the soloist and choir sing together. To achieve compositional and dramatic unity, there was a need to involve additional means in addition to the cross-cutting image of Mother Goose, since the Jack’s plot is deprived of the consistent development of events. This function is performed by several themes: «fairy tale» (in the future it is associated with the appearance of fairies and elves), «pastoral» (its emergence is marked by the remark Andante Pastorale), the theme of Jack, the dance motive, and the theme of King Cole. They are exhibited in the overture for the fi rst time. When the act begins, they are joined by the themes of Mother Goose and Thrushes. For the fi rst time, most of the themes are conducted in the overture. This determines the suite character of its structure: 6 episodes that contrast with each other by tempo. The piano part plays an important role in the operetta. It presents the leading themes, the main image-bearing and poetic motives, and supports the performers in the vocal appearances. The revealed signs give grounds to consider the English-language children’s operetta a national model of opera for children-performers. Conclusions. In the English-speaking countries, particularly in the USA, at the end of the 19th – in the fi rst half of the 20th century the tradition to perform operettas at schools was formed. This works from their form and contents were similar to compositions which were called children’s operas (operas for children-performers) in Europe. An analysis of The House that Jack Built by J. L. Gaynor allows us to interpret the author’s genre name in its original linguistic meaning – «small opera». A signifi cant number of such works still remain beyond the attention of scholars and require a thorough study both in historical and in theoretical directions.

La producción de conocimiento a través de la investigación académica está siendo cada vez más exigida y cuestionada, en un entorno de crisis socio-económica e institucional generalizada de la Universidad. Por su parte, la investigación académica se ve exigida para dar respuesta a las presiones y necesidades del entorno, concretamente a las prioridades de las organizaciones productivas y del mercado. Al mismo tiempo, la investigación en gestión, contabilidad y finanzas es cuestionada por conseguir un impacto muy modesto, en términos de relevancia y difusión de sus hallazgos a un público más amplio, que trascienda el contexto de los mismos investigadores. Estas exigencias y cuestionamientos reclaman una reflexión detenida por parte de los académicos; por ello, en este editorial queremos aportar algunos breves elementos para el debate.Boaventura de Sousa santos, uno de los más influyentes pensadores sociales contemporáneos, ha senalado que actualmente la Universidad vivencia una crisis de hegemonía, una crisis de legitimidad y una crisis institucional (De Sousa, 2007).Hoy en día, el conocimiento autorizado ya no se genera solo en la Universidad, lo que tiene implicaciones profundas en su centralidad-hegemonía y en la forma en que la sociedad misma ve a esta institución. En la sociedad del conocimiento, las empresas y otras entidades privadas parecen preocuparse por la creación del conocimiento, tanto o más que la Universidad y el propio Estado. La presión por la innovación atraviesa todo el tejido societal y no se entiende por fuera de la generación de nuevo conocimiento, con capacidad de ser usado y asimilado colectivamente. Allí, la tensión entre conocimiento e interés toma un realce particular, puesto que los fines altruistas y los mecanismos que acompañaron los procesos de producción de conocimiento en la "academia" se ven desplazados y/o transformados en un escenario de nuevas prioridades económicas (Habermas, 1982).La crisis de legitimidad de la Universidad surge en el marco de las contradicciones sociales y de las funciones y valores que la misma Universidad asumió en la modernidad (De sousa, 2007). El proyecto de educación de masas, bajo el amparo de los valores de la ilustración, implicaba el aumento de la cobertura de la educación superior como un camino hacia la construcción de una sociedad más democrática e incluyente. Pero las relaciones complejas entre educación para el ascenso social, reproducción de los valores dominantes y de la alta cultura y la prioridad en las necesidades económicas (mano de obra para el trabajo) han llevado a que, sobre todo en los países industrializados, la educación superior no logre colmar todas las expectativas de retornos económicos y/o de desarrollo democrático de tales sociedades.Finalmente, la crisis institucional de la Universidad deviene de la contradicción de sus valores, entre ellos la autonomía necesaria para la búsqueda del conocimiento comprometido solo con el bien común y la verdad, y las exigencias crecientes de eficiencia y de gestión bajo los parámetros de las entidades empresariales. La transformación paulatina de las prioridades y valores de las clases dominantes llevó a que la Universidad lentamente perdiera el compromiso estatal de su financiación, teniendo que desplegar procesos de gestión de sus ingresos y costos. La búsqueda de ingresos hace que sus actividades misionales se adapten al mercado, por ejemplo, con impactos profundos en la creación de conocimiento desinteresado, en la formación para la ciudadanía o en el cultivo de la estética y las artes liberales (Nussbaum, 2010).De esta manera, la conjunción de estas crisis conduce a la situación social, institucional y económica que hoy viven las universidades, no solo en Colombia, sino en gran parte del mundo industrializado, que podemos catalogar francamente como "crítica". Es en tal contexto en el que la presión por desarrollar agendas de investigación más "aplicadas" o cercanas a las necesidades de las organizaciones y del mercado se torna prioritaria en las instituciones universitarias. Es también en este contexto donde la relevancia es entendida como la consecución de aplicaciones concretas de los resultados de investigación a problemas organizacionales, con retornos económico-financieros positivos conseguidos en el mercado (p.e. patentes, contratos de [&D, etc.).Es innegable que en el ámbito de las ciencias de gestión, de la contabilidad y de las finanzas, la naturaleza de tales conocimientos reclama un vínculo muy profundo con el mundo organizacional. No obstante, debemos diferenciar con cuidado la búsqueda del conocimiento y la verdad, de la generación de publicidad o de la producción de relatos que pretenden legitimidad. La investigación aplicada se torna más relevante y confiable para conocer el mundo empresarial, cuando está soportada en marcos conceptuales y estructuras teóricas robustas, que son propias de la investigación básica y que permiten entregar sentido explicativo y comprensivo a los eventos empíricos; todo ello implica que no solo la aplicación es válida para la investigación en nuestras disciplinas. Pero al mismo tiempo, la investigación aplicada puede poner a prueba los referentes teóricos traídos de otras latitudes y ser germen para la construcción de un conocimiento endógeno de nuestra realidad tropical (Mora-Osejo y Fals-Borda, 2004).De esta manera, el vínculo entre Universidad, por una parte, y entorno empresarial y mercado, por otra, requiere ser permanente repensado y reconstruido. Debemos comprender que los tiempos de la generación del conocimiento no necesariamente siguen los ritmos de la producción empresarial, expuesta a las presiones para la subsistencia económica en la lucha del mercado. Pero también debemos entender que la comprensión, intervención y transformación de nuestra realidad reclama un proceso disciplinado y comprometido con la entrega de resultados tangibles, que repercutan en sugerencias y estrategias de acción para el mediano y largo plazo.La relevancia de los resultados de investigación y la efectividad de su difusión vienen siendo también discutidas. Una evaluación de las diferentes posturas no puede perder de vista el contexto de crisis que la Universidad afronta. En el fondo, la relevancia de la investigación universitaria es cuestionada dadas las crisis financiera y de legitimidad que esta institución enfrenta. El debate por el sentido de la publicación universitaria y académica debe ser abordado, sin perder de vista los matices sociológicos que están inmersos en la producción del conocimiento. De ello se desprende la conveniencia de admitir que los académicos son individuos que actúan en estructuras sociales y con ciertos grados de agencia-autonomía; por tanto, también pueden ser más o menos altruistas, utilitaristas, interesados u oportunistas.Si bien la difusión de los resultados de investigación primero requiere del lente experto de los académicos, para garantizar el carácter científico de los hallazgos y la autorregulación responsable, no es menos cierto que la investigación debe trascender el reducido espacio de los claustros, impactando a los actores con capacidad de decisión política y económica y a la opinión pública. No obstante, no solo la Universidad está en crisis. La sociedad enfrenta una crisis de iniquidad y valores democráticos que tiene pocos precedentes. En un escenario como estos, la verdad puede ser incómoda, no solo para el poder económico (que hoy se funde con el poder político) sino para los propios ciudadanos. El riesgo sería confundir relevancia y pertinencia, solo con conocimiento interesado y retórica de legitimación sobre el statu quo en el mundo organizacional y en el mercado global.Por estas razones, entre otras, desde esta tribuna que es [NNOVAR, invitamos a los académicos iberoamericanos de las ciencias de gestión (así como de otras ciencias sociales), para plantear debates y reflexiones que permitan aumentar nuestra comprensión de la realidad organizacional de la región. Estamos comprometidos con el conocimiento científico para el bienestar social y para la construcción de procesos organizacionales más sostenibles. Trabajaremos en conseguir que la revista no solo sea un medio de difusión dirigido a académicos, sino en que la base de profesionales, empresarios y tomadores de decisiones públicas que acceden a nuestra publicación sea cada vez mayor.En este número presentamos diez (10) artículos de investigación, agrupados en tres (3) de nuestras tradicionales secciones: Estrategia y organizaciones, Contabilidad y finanzas, y Educación y empleo.En la primera sección, Estrategia y organizaciones, recogemos cuatro (4) artículos.Desde Uruguay, el profesor Luis silva-Domingo aporta su investigación bajo el título "Management Control: Unsolved Problems and Research Opportunities". En este trabajo el autor identifica un conjunto de conceptos centrales para el control de gestión, llamando la atención sobre la importancia del consenso entre los académicos e investigadores para fortalecer este campo de conocimientos. Los tres conceptos clave que requieren mayores acuerdos son: el problema del control de gestión; la definición y caracterización de los mecanismos del control de gestión; y, finalmente, el alcance de los sistemas de control de gestión.En una colaboración hispano-chilena, los profesores Patricia Huerta, Paloma Almodóvar, Liliana Pedraja, José Navas y Sergio Contreras nos presentan el artículo "Factores que impactan sobre los resultados empresariales: un estudio comparativo entre empresas chilenas y españolas". El trabajo realiza una importante revisión de la literatura sobre los factores que definen el resultado empresarial. Al mismo tiempo, lleva a cabo una muy juiciosa contrastación en empresas de los dos países estudiados, entregando evidencia empírica sobre los factores que influyen decisivamente en los resultados empresariales.Las profesoras españolas Natalia Vila e [Nés Kúster contribuyen a este número con el trabajo titulado "¿Conduce la internacionalización al éxito de una empresa familiar?: aplicación al sector textil". Esta investigación buscó contrastar en las empresas del sector textil espanol, un sector altamente competitivo, la manera en que la internacionalización promovió el éxito empresarial. Para ello, asumió como variables definitorias del éxito empresarial: los resultados empresariales (volumen de ventas, nivel de beneficios, etc.) y los indicadores de desempeño (satisfacción de los clientes, reputación percibida, calidad, etc.). La investigación se basó en encuestas realizadas a 154 gerentes de empresas textiles de España.Para cerrar esta sección, se presenta en la revista el artículo titulado "Project Management in Development Cooperation. Non Governmental Organizations", de autoría de los profesores Maricela Montes-Guerra, Aida De-Miguel, Amaya Pérez-Ezcurdia, Faustino Gimena y Mauricio Díez-silva, fruto de una colaboración colombo-espanola. En esta investigación, los autores llaman la atención sobre la relevancia de la gestión de proyectos para las iniciativas de apoyo y cooperación internacional al desarrollo. En particular, el trabajo permite concluir que la gestión de proyectos puede mejorar la eficiencia y la rendición de cuentas de tales proyectos.Nuestra sección de Contabilidad y finanzas está constituida, igualmente, por cuatro (4) artículos científicos.El primer artículo de esta sección es de autoría del profesor colombiano Javier Humberto Ospina Holguín, y se titula "Medidas dinámicas de predictibilidad en el índice S&P 500 y sus determinantes". Esta investigación buscó medir la predictibilidad del índice Standard and Poor's 500. Para ello construyó un algoritmo basado en medidas dinámicas de predictibilidad. La investigación concluye que el mercado no es estáticamente predecible, sino que la predictibilidad evoluciona dinámicamente, lo que corrobora la hipótesis teórica de la tendencia adaptativa del mercado.Los profesores españoles Fernando Azcárate Llanes, Manuel Fernández Chulián y Francisco Carrasco Fenech aportan el trabajo "Memorias de sostenibilidad e indicadores integrados: análisis exploratorio sobre características definitorias. Una reflexión crítica". Esta investigación buscó caracterizar las empresas que publican memorias de sostenibilidad (informes de desarrollo sostenible, siguiendo la guía No. 3 del Global Reporting [niciative-GR[ G3-) y que contienen indicadores integrados. A partir de la realización de un análisis clúster, el trabajo permitió agrupar a las empresas que producen los informes (memorias) de mayor calidad. Se concluye que las memorias muestran deficiencias, pese al alto reconocimiento que, en materia de Responsabilidad social, tienen las empresas que las emiten.Bajo el título "El empleo de la Webmetría para el análisis de los indicadores de desempeño y posición financiera de la empresa: un análisis exploratorio en diversos sectores económicos de los Estados Unidos", presentamos la colaboración de los profesores Esteban Romero Frías, Liwen Vaughan y Lázaro Rodríguez Ariza, de universidades de España y Canadá. Esta investigación busca identificar si existe relación entre las variables financieras y los enlaces recibidos por empresas de diversos sectores económicos. El trabajo buscó extender los hallazgos previos de la literatura, más allá de empresas del sector de tecnología, particularmente en el contexto estadounidense. Los resultados muestran que existe un vínculo entre el número de enlaces que reciben las páginas web de las empresas y su dimensión económica (posición y desempeño financiero).Cierra esta sección con la investigación de los profesores espanoles Belén Vallejo-Alonso, José Domingo García-Merino y Gerardo Arregui-Ayastuy, artículo titulado "Motives for Financial Valuation of Intangibles and Business Performance in SMEs". Este trabajo buscó analizar la relación existente entre los motivos que llevan a la valoración de los intangibles y el desempeño de las pequeñas y medianas empresas (Pymes). La investigación empírica implicó entrevistar telefónicamente a 369 gerentes financieros de Pymes españolas y la vinculación de sus respuestas con el análisis de la información financiera de tales empresas. Los resultados muestran que las Pymes consideran que la valoración financiera de sus intangibles permite un mejor desempeño.En la sección de Educación y empleo, para este número, publicamos dos (2) resultados de investigación.El primer trabajo se denomina "¿Es posible potenciar la capacidad de liderazgo en la universidad?", fruto de la colaboración de los profesores Carmen Delia Dávila Quintana, José-Ginés Mora, Pedro Pérez Vázquez y Luis Eduardo Vila, quienes están vinculados con universidades de España y el Reino Unido. El trabajo analizó la importancia de la educación superior en el comportamiento de los egresados en el puesto de trabajo, particularmente en las dimensiones del liderazgo orientado a las tareas, las relaciones y al cambio. A partir de modelos de ecuaciones estructurales, los resultados muestran que el comportamiento de los egresados como líderes depende crucialmente de determinadas competencias clave.El segundo artículo, fruto del trabajo de las investigadoras colombianas Silvia Morales Gualdrón y Astrid Giraldo Gómez, se titula "Análisis de una innovación social: el Comité Universidad Empresa Estado del Departamento de Antioquia (Colombia) y su funcionamiento como mecanismo de interacción". La investigación buscó caracterizar el Comité Universidad Empresa Estado (CUEE) del Departamento de Antioquia, desde la teoría de redes y la teoría de la comunicación funcional. La metodología observada fue cualitativa y se basó en entrevistas a profundidad y en la triangulación de documentos, tales como las actas del CUEE. El trabajo concluye que el CUEE opera como una red de conocimiento en el que la comunicación, la deliberación, la confianza y la negociación se construyen por medio del consenso.Como siempre, estamos seguros de que nuestros lectores encontrarán valiosos estos trabajos. También, partimos de reconocer que nuestros colaboradores continúan aportando a la comprensión de la dinámica organizacional y socioeconómica, en un ambiente complejo y retador como el que enfrenta hoy la Universidad internacional e iberoamericana.

Luke-Acts was written during the period after the destruction of the second temple, when, for most Jews, hopes for future restoration were conceived largely in terms of rebuilding the temple and city of Jerusalem and resuming the cultic life associated therewith. Against this background Luke poses an alternative vision, in which the divine presence associated previously with the [foreign font omitted] is seen no longer as localised but as dispersed. The Holy Spirit manifested in the life and expansion of the Church transcends and supersedes the notion of sacred space associated with the Zion traditions.

In-depth studies of molecular pathways have provided insights to explore therapeutic targets for treating hypertension as a complex disease. We previously identified PDE5 as an interacting partner with RhoBTB1 protein in aortic smooth muscle cells (SMCs). RhoBTB1 regulates PDE5 activity and therefore intracellular cGMP levels, and restoration of RhoBTB1 expression in RhoBTB1-deficient states results in improvement of cardiovascular status in a mouse model of hypertension. Here we identified the specific regions of RhoBTB1 that are responsible for the recruitment of PDE5. Our goal is to use this as a guide to identify additional RhoBTB1 interacting proteins which play important roles in cardiovascular function in the hope their identification may open novel therapeutic avenues against hypertension and associated pathologies. We hypothesize that RhoBTB1 acts as an adaptor for Cullin-3 E3 ring ubiquitin ligase complex, where Cullin-3 functions as “scaffold” which delivers PDE5 (and other targets) to Cullin-3 complex followed by ubiquitination and proteasomal degradation. We generated several truncations in full length RhoBTB1, splitting it into its GTPase, BTB1, BTB2, Carboxyl-terminal (CT), BTB1-BTB2, and BTB1-BTB2-CT domains. To check the preferred binding interface for PDE5, we co-transfected HEK293 cells with epitope tagged PDE5 and separately tagged truncations of RhoBTB1, and analyzed the interaction between PDE5 and RhoBTB1 domains using co-immunoprecipitation assays. Our result shows that BTB1-BTB2-C domain of RhoBTB1 is the preferred binding region for PDE5. The BTB1-BTB2 domain lacking the CT was unable to bind to PDE5. Next, we will utilize stable isotope labeling by amino acids in cell culture (SILAC) followed by proteomic profiling to identify additional targets and/or adaptors involved in the binding of PDE5 and RhoBTB1. Similarly, we will tag specific domains of RhoBTB1 using the ascorbate peroxidase (APEX2) fusion system followed by proteomic profiling.

The vices rampant now among students in Nigeria secondary schools, such as acts of indiscipline, stealing, cheating, truancy, rioting, cultism, and raping, together with population explosion, call for special skills on the part of the school administrators to be able to cope with these challenges. Consequently, this paper examines the uniqueness of the principals position to make or mar the image of the educational system and the need for these principals to be well equipped to meet these challenges in the educational system of the third world, with particular reference to Nigeria. This is so because it is now clear that the pre-service skills acquired by present school administrators, through formal education, may not be adequate to meet with these sustainable challenges. Recommendations on probable improvement of these staff development programmes for effective and efficient performance of these principals on their jobs concluded this paper.

AbstractLong noncoding RNAs (lncRNAs) have been demonstrated to be important regulators during the osteogenic differentiation of mesenchymal stem cells (MSCs). We analyzed the lncRNA expression profile during osteogenic differentiation of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) and identified a significantly downregulated lncRNA RP11-527N22.2, named osteogenic differentiation inhibitory lncRNA 1, ODIR1. In hUC-MSCs, ODIR1 knockdown significantly promoted osteogenic differentiation, whereas overexpression inhibited osteogenic differentiation in vitro and in vivo. Mechanistically, ODIR1 interacts with F-box protein 25 (FBXO25) and facilitates the proteasome-dependent degradation of FBXO25 by recruiting Cullin 3 (CUL3). FBXO25 increases the mono-ubiquitination of H2BK120 (H2BK120ub) which subsequently promotes the trimethylation of H3K4 (H3K4me3). Both H2BK120ub and H3K4me3 form a loose chromatin structure, inducing the transcription of the key transcription factor osterix (OSX) and increasing the expression of the downstream osteoblast markers, osteocalcin (OCN), osteopontin (OPN), and alkaline phosphatase (ALP). In summary, ODIR1 acts as a key negative regulator during the osteogenic differentiation of hUC-MSCs through the FBXO25/H2BK120ub/H3K4me3/OSX axis, which may provide a novel understanding of lncRNAs that regulate the osteogenesis of MSCs and a potential therapeutic strategy for the regeneration of bone defects.