bluuebunny/crossref_metadata_2025 huggingface dataset:
Josip Široki: Singer and Transcriber at the Same Time
Authors: Tiefenthaler Vera
Published: December 2010

The author’s aim was to discover what influence Josip Široki’s activities have had on folk song collection. This is of special interest because he was working on a collection of folk songs at the same time that the Austrian program Austrian Folk Songs was being carried out. It is shown that Široki’s methods differed significantly from the common methods applied at his time. In addition, light is shed on Široki’s possible motivation to collect folk songs and how his work was influenced by other disciplines.
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Avtorica poskuša razkriti, kako pomembna je dejavnost Josipa Širokija za zbirko ljudskih pesmi. Ta je namreč posebnega pomena, saj je pripravljal zbirko ljudskih pesmi v času, ko se je izvajal avstrijski projekt Das Volkslied in Österreich. Avtorica ugotavlja, da so se Širokove metode zelo razlikovale od splošnih metod tistega časa. Ob tem osvetljuje morebitne spodbude za zbirko ljudskih pesmi in govori o tem, kako so na njegovo delo vplivale druge vede.
Metamorphoses of Slovenian Folk Dance
Authors: Ramovš Mirko
Published: December 2010

Similar to other phenomena in folk culture, folk dance has been subject to different influences throughout its existence that changed its form, structure, style, and function in people’s everyday and festive lives. This paper analyses the changes that have taken place and tries to categorize them and establish reasons for them. The paper is primarily based on dances recorded after World War II, in combination with materials collected in the program of the Committee for the Collection of Slovenian Folk Songs at the beginning of the 20th century.
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Tako kot vsi pojavi ljudske kulture je bil tudi ples v teku svojega obstoja podvržen različnim vplivom, ki so spreminjali njegovo obliko, strukturo, slog ter vlogo v vsakdanjem in prazničnem življenju. Prispevek analizira te spremembe, jih skuša opredeliti in poiskati vzroke. Opira se večinoma na plese, zapisane po 2. svetovni vojni, v dopolnitev pa služi gradivo, nabrano v začetku 20. stoletja v okviru akcije Odbora za nabiranje slovenskih narodnih pesmi.
The Folkdances of the Western Polissia Region of Ukraine: Traditions and Innovations
Authors: Fedun Iryna
Published: December 2010

The Western Polissia ethnographic region of northwest Ukraine has a comparatively well-preserved traditional culture due to its naturally inaccessible woods and swamps. The territory is also unique because many scholars believe that it represents the original Slavic homeland. This article analyzes changes in the non-ritual dance repertoire of musicians of the Western Polissia region. New dances (e.g., the pol′ka, krakoviak, oberek, val′s, podispan, barynia, iablochko, na riechien′ku, karapiet, etc.) were incorporated due to the influence of national minorities and other people living in the area, as well as the diffusion of urban culture and the impact of mass-media on more traditional local forms such as the krutak, hrechka, etc.
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Etnografsko območje Zahodnega Polesja v severozahodni Ukrajini ima zaradi slabe dostopnosti (gozdovi in močvirja) zelo dobro ohranjeno tradicionalno kulturo. Poleg tega je po mnenju številnih znanstvenikov Zahodno Polesje posebno območje, ker predstavlja prvotno domovino Slovanov. V prispevku obravnava avtorica spremembe v repertoarju plesov, ki niso povezani z obredi, tega območja. Vplivi narodnih manjšin in sosednjih narodov, pa tudi razširitev mestne kulture in množičnih medijev so pripomogli k temu, da so se tradicionalnim lokalnim oblikam, kot so krutak, hrechka ipd., pridružili novi plesi, npr. polka, krakovjak, oberek, valček idr.
Folk Song Today: Between Function and Aesthetics
Authors: Golež Kaučič Marjetka
Published: December 2010

The paper deals with the question of the classification of the folk song today. With regard to its lost original context, has the folk song really become no more than an esthetic artifact, or have new circumstances reconstructed the context and thus added a new functional dimension to the folk song? In addition, the author discusses the new communication channels used to reintegrate the folk song in its traditional environment based on the example of the song “Riba Faronika nosi svet” (Faronika the Fish Bears the World).
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Razprava se loteva vprašanja o tem, v katero semantično polje uvrščamo ljudsko pesem danes. Ali je zaradi izgube izvirnega konteksta res samo še estetsko dejstvo ali pa zaradi novih okoliščin, ki rekonstruirajo sam kontekst, ponovno lahko opazujemo tudi njeno funkcijsko razsežnost? Avtorica se v razpravi sprašuje tudi o novih komunikacijskih kanalih, po katerih ljudska pesem (na primeru pesmi Riba Faronika nosi svet) ponovno vstopa v tradicionalno okolje.
Why Play and Sing? The Role of Folk Games and Folk Songs in Everyday Life
Authors: Lázár Katalin
Published: December 2010

Playing helps us in learning and developing more kinds of skills, further in developing our emotional world, not only in traditional society but in any time and any place. Singing strengthens collective consciousness and identity. Besides, playing and singing as basic forms of entertainment assure enjoying ourselves to us. We have to learn and do them for the sake of living a perfect life: to be able to express our joy and to amuse ourselves.
***
Igranje pomaga pri učenju in razvijanju številnih sposobnosti, pa tudi pri razvoju čustvenega sveta, ne le v tradicionalni družbi, ampak v katerem koli prostoru in času. Petje krepi kolektivno zavest in identiteto. Poleg tega igranje in petje kot osnovni obliki zabave zagotavljata, da uživamo tudi sami s seboj. Zato se ju moramo učiti in s petjem in igranjem izražati svoje veselje in se zabavati.
Folk Heritage and Contemporary (Re)Production: A Musical Story for Three Minutes and Twelve Seconds
Authors: Narat Boštjan
Published: December 2010

V prispevku je reflektirana povezava med ljudsko in sodobno glasbeno izkušnjo, pri čemer pozornost ni usmerjena na ohranjanje tradicije v smislu arhiviranja, pač pa predvsem na (ne)možnost rekonstrukcije žive izkušnje. Le-ta postane mogoča takrat, ko je stik med preteklim (ljudskim) in sedanjim utemeljen v občutku za izvorno identiteto – ljudska in sodobna godba se nahajata v istem horizontu (razumevanja) glasbe –, kar ima za posledico večjo prilagodljivost v poustvarjalski praksi, ki je nujen pogoj za podoživetje pretekle glasbene situacije.
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This paper deals with the relationship between the experience of folk and that of contemporary music. The author’s attention is devoted primarily to the possibility of reconstructing a live experience rather than sticking to a tradition in the sense of archiving. Such an experience becomes possible when the connection between past (folk music) and present is based on a feeling of original identity – folk and contemporary music exist in the same musical horizon – that results in a better adaptability of the re-creational praxis, which is the preliminary for re-experiencing the past musical situation.
The Popularization of Slovenian Folk Music between the Local and Global: Redemption or Downfall of National Heritage
Authors: Juvančič Katarina
Published: December 2010

Through cultural and political changes, and different periods of time and locations, this article observes the dynamic variation of folk music in the local, national, and global context and illustrates this with examples. It focuses on the role of cultural policy, scholarship, and other factors in the process of the nationalization of folk music in the past and present, and questions the concept and use of the term “tradition” in Slovenian folklore and folk revival discourses.
***
S pomočjo kulturnih, političnih, časovnih in prostorskih premen avtorica opazuje dinamični preplet ljudske glasbe v lokalnem, nacionalnem in globalnem kontekstu ter jih pojasnjuje na podlagi konkretnih primerov. Pozornost usmeri na vlogo kulturne politike, znanosti in drugih akterjev v procesu nacionalizacije ljudske glasbe v preteklosti in danes, pri čemer podrobneje preizprašuje koncept tradicije in njegovo rabo v slovenskih folklorističnih in folk revival diskurzih.
The Reception of Folk Songs by Children and Young People in Slovenia
Authors: Jakop Tjaša
Published: December 2010

The aim of this paper is to ascertain the extent to which folk songs are part of the lives of children and young people, from primary school through secondary school and on to university. The research was carried out with the help of written surveys. The article concludes that young people are still fairly well acquainted with this part of folk heritage, although their awareness is often due to modern interpretations and arrangements by Slovenian musicians.
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Namen prispevka je ugotoviti, v kakšni meri je ljudska pesem prisotna v življenju otrok in mladostnikov od osnovne prek srednje šole do fakultete. Raziskavo sem opravila s pomočjo pisne ankete na terenu in ugotovila, da mladi še vedno precej dobro poznajo tovrstno ljudsko blago, pa četudi v novi preobleki, tj. kot sodobne interpretacije in priredbe slovenskih glasbenikov.
From oxidation to Paf the Dog: mental images of student engineers in EFL vocabulary association and retention
Authors: Boulton Alex
Published: December 2010

On prétend souvent que le lexique constitue un des plus grands problèmes pour l’apprenant d’une langue étrangère (L2), certainement dû en partie à l’emploi répandu de techniques inefficaces. De nombreux linguistes en didactique des langues étrangères orientent ainsi leurs recherches vers le lien entre la longévité des traces mémorielles et la force affective des images et associations mentales. Dans cet article, nous analysons différents types d’images et d’associations produites spontanément par des apprenants de l’anglais L2 sans formation dans ces techniques. Lors d’une première expérience, une liste de mots est présentée visuellement et sans ordre apparent ; les taux de rappel soulignent un certain nombre de phénomènes psychologiques. Dans une deuxième expérience, nous étudions la production et le rappel ultérieur d’associations lexicales fournies par l’apprenant. Nous en tirons certaines conclusions pour les stratégies lexicales ainsi que pour l’enseignement et l’apprentissage du vocabulaire L2.
Provision of Continuous Maturation Signaling to Dendritic Cells by RIG-I–Stimulating Cytosolic RNA Synthesis of Sendai Virus
Authors: Okano Shinji , Yonemitsu Yoshikazu , Shirabe Ken , Kakeji Yoshihiro , Maehara Yoshihiko , Harada Mamoru , Yoshikai Yasunobu , Inoue Makoto , Hasegawa Mamoru , Sueishi Katsuo
Published: December 2010

Dendritic cell (DC)-based immunotherapy has potential for treating infections and malignant tumors, but the functional capacity of DC must be assessed in detail, especially maturation and Ag-specific CTL priming. Recent reports suggest that DC that are provided with continuous maturation signals in vivo after transfer into patients are required to elicit the full DC functions. We demonstrate in this study that the rSendai virus vector (SeV) is a novel and ideal stimulant, providing DC with a continuous maturation signal via viral RNA synthesis in the cytosol, resulting in full maturation of monocyte-derived DC(s). Both RIG-I–dependent cytokine production and CD4 T cell responses to SeV-derived helper Ags are indispensable for overcoming regulatory T cell suppression to prime melanoma Ag recognized by T cell-1–specific CTL in the regulatory T cell abundant setting. DC stimulated via cytokine receptors, or TLRs, do not show these functional features. Therefore, SeV-infected DC have the potential for DC-directed immunotherapy.
TNF Receptor-1 Is Required for the Formation of Splenic Compartments during Adult, but Not Embryonic Life
Authors: Milićević Novica M. , Klaperski Karola , Nohroudi Klaus , Milićević Živana , Bieber Katja , Baraniec Babett , Blessenohl Maike , Kalies Kathrin , Ware Carl F. , Westermann Jürgen
Published: December 2010

Lymphotoxin β-receptor (LTβR) and TNF receptor-1 (TNFR1) are important for the development of secondary lymphoid organs during embryonic life. The significance of LTβR and TNFR1 for the formation of lymphoid tissue during adult life is not well understood. Immunohistochemistry, morphometry, flow cytometry, and laser microdissection were used to compare wild-type, LTβR−/−, TNFR1−/− spleens with splenic tissue that has been newly formed 8 wk after avascular implantation into adult mice. During ontogeny, LTβR is sufficient to induce formation of the marginal zone, similar-sized T and B cell zones, and a mixed T/B cell zone that completely surrounded the T cell zone. Strikingly, in adult mice, the formation of splenic compartments required both LTβR and TNFR1 expression, demonstrating that the molecular requirements for lymphoid tissue formation are different during embryonic and adult life. Thus, interfering with the TNFR1 pathway offers the possibility to selectively block the formation of ectopic lymphoid tissue and at the same time to spare secondary lymphoid organs such as spleen and lymph nodes. This opens a new perspective for the treatment of autoimmune and inflammatory diseases.
CpG Promotes Cross-Presentation of Dead Cell-Associated Antigens by Pre-CD8α+ Dendritic Cells
Authors: de Brito Christelle , Tomkowiak Martine , Ghittoni Raffaella , Caux Christophe , Leverrier Yann , Marvel Jacqueline
Published: December 2010

Cross-presentation of cell-associated Ags by dendritic cells (DC) plays an important role in immunity. DC in lymphoid tissues are short lived, being continuously replaced by precursors that proliferate and differentiate locally. Paradoxically, although TLR ligands promote immune responses and stimulate DC replenishment, they impair the cross-priming capacity of terminally differentiated splenic CD8α+ DC, the major subset involved in cross-priming. In this study, we have investigated the cross-presentation capacity of newly generated murine DC and especially immediate precursors of CD8α+ DC. We show that these DC do not cross-present Ag from dead cells unless stimulated by TLR ligands before Ag capture. TLR ligand CpG induced the expression of costimulatory molecules required for CD8 T cell activation but also regulated the intracellular mechanisms of cross-presentation such as Ag degradation rates without regulating Ag uptake. GM-CSF, an inflammatory cytokine associated with infections, also promoted cross-presentation acquisition by pre-CD8α+ DC and synergized with TLR9 ligand. The concept that TLR ligands as well as inflammatory cytokines promote the acquisition of cross-presenting properties by pre-CD8α+ DC has important implications during immune responses and when considering the use of these cells for vaccination.
In Situ B Cell-Mediated Immune Responses and Tubulointerstitial Inflammation in Human Lupus Nephritis
Authors: Chang Anthony , Henderson Scott G. , Brandt Daniel , Liu Ni , Guttikonda Riteesha , Hsieh Christine , Kaverina Natasha , Utset Tammy O. , Meehan Shane M. , Quigg Richard J. , Meffre Eric , Clark Marcus R.
Published: December 2010

The most prevalent severe manifestation of systemic lupus erythematosus is nephritis, which is characterized by immune complex deposition, inflammation, and scarring in glomeruli and the tubulointerstitium. Numerous studies indicated that glomerulonephritis results from a systemic break in B cell tolerance, resulting in the local deposition of immune complexes containing Abs reactive with ubiquitous self-Ags. However, the pathogenesis of systemic lupus erythematosus tubulointerstitial disease is not known. In this article, we demonstrate that in more than half of a cohort of 68 lupus nephritis biopsies, the tubulointerstitial infiltrate was organized into well-circumscribed T:B cell aggregates or germinal centers (GCs) containing follicular dendritic cells. Sampling of the in situ-expressed Ig repertoire revealed that both histological patterns were associated with intrarenal B cell clonal expansion and ongoing somatic hypermutation. However, in the GC histology, the proliferating cells were CD138−CD20+ centroblasts, whereas they were CD138+CD20low/− plasmablasts in T:B aggregates. The presence of GCs or T:B aggregates was strongly associated with tubular basement membrane immune complexes. These data implicate tertiary lymphoid neogenesis in the pathogenesis of lupus tubulointerstitial inflammation.
Dragon (Repulsive Guidance Molecule b) Inhibits IL-6 Expression in Macrophages
Authors: Xia Yin , Cortez-Retamozo Virna , Niederkofler Vera , Salie Rishard , Chen Shanzhuo , Samad Tarek A. , Hong Charles C. , Arber Silvia , Vyas Jatin M. , Weissleder Ralph , Pittet Mikael J. , Lin Herbert Y.
Published: December 2010

Repulsive guidance molecule (RGM) family members RGMa, RGMb/Dragon, and RGMc/hemojuvelin were found recently to act as bone morphogenetic protein (BMP) coreceptors that enhance BMP signaling activity. Although our previous studies have shown that hemojuvelin regulates hepcidin expression and iron metabolism through the BMP pathway, the role of the BMP signaling mediated by Dragon remains largely unknown. We have shown previously that Dragon is expressed in neural cells, germ cells, and renal epithelial cells. In this study, we demonstrate that Dragon is highly expressed in macrophages. Studies with RAW264.7 and J774 macrophage cell lines reveal that Dragon negatively regulates IL-6 expression in a BMP ligand-dependent manner via the p38 MAPK and Erk1/2 pathways but not the Smad1/5/8 pathway. We also generated Dragon knockout mice and found that IL-6 is upregulated in macrophages and dendritic cells derived from whole lung tissue of these mice compared with that in respective cells derived from wild-type littermates. These results indicate that Dragon is an important negative regulator of IL-6 expression in immune cells and that Dragon-deficient mice may be a useful model for studying immune and inflammatory disorders.
CR2+ Marginal Zone B Cell Production of Pathogenic Natural Antibodies Is C3 Independent
Authors: Woods Keith M. , Pope Michael R. , Hoffman Sara M. , Fleming Sherry D.
Published: December 2010

Intestinal ischemia-reperfusion (IR)–induced damage requires complement receptor 2 (CR2) for generation of the appropriate natural Ab repertoire. Pathogenic Abs recognize neoantigens on the ischemic tissue, activate complement, and induce intestinal damage. Because C3 cleavage products act as ligands for CR2, we hypothesized that CR2hi marginal zone B cells (MZBs) require C3 for generation of the pathogenic Abs. To explore the ability of splenic CR2+ B cells to generate the damaging Ab repertoire, we adoptively transferred either MZBs or follicular B cells (FOBs) from C57BL/6 or Cr2−/− mice into Rag-1−/− mice. Adoptive transfer of wild type CR2hi MZBs but not CR2lo FOBs induced significant damage, C3 deposition, and inflammation in response to IR. In contrast, similarly treated Rag-1−/− mice reconstituted with either Cr2−/− MZB/B1 B cells (B1Bs) or FOBs lacked significant intestinal damage and displayed limited complement activation. To determine whether C3 cleavage products are critical in CR2-dependent Ab production, we evaluated the ability of the natural Ab repertoire of C3−/− mice to induce damage in response to IR. Infusion of C3−/− serum into Cr2−/− mice restored IR-induced tissue damage. Furthermore, Rag-1−/− mice sustained significant damage after infusion of Abs from C3−/− but not Cr2−/− mice. Finally, adoptive transfer of MZBs from C3−/− mice into Rag-1−/− mice resulted in significant tissue damage and inflammation. These data indicate that CR2 expression on MZBs is sufficient to induce the appropriate Abs required for IR-induced tissue damage and that C3 is not critical for generation of the pathogenic Abs.
Pyk2 Is Required for Neutrophil Degranulation and Host Defense Responses to Bacterial Infection
Authors: Kamen Lynn A. , Schlessinger Joseph , Lowell Clifford A.
Published: December 2010

The appropriate regulation of neutrophil activation is critical for maintaining host defense and limiting inflammation. Polymorphonuclear neutrophils (PMNs) express a number of cytoplasmic tyrosine kinases that regulate signaling pathways leading to activation. One of the most highly expressed, but least studied, kinases in PMNs is proline rich kinase 2 (Pyk2). By analogy to the related focal adhesion kinase, Pyk2 has been implicated in regulating PMN adhesion and migration; however, its physiologic function has yet to be described. Using pyk2−/− mice, we found that this kinase was required for integrin-mediated degranulation responses, but was not involved in adhesion-induced cell spreading or activation of superoxide production. Pyk2-deficient PMNs also manifested reduced migration on fibrinogen-coated surfaces. The absence of Pyk2 resulted in a severe reduction in paxillin and Vav phosphorylation following integrin ligation, which likely accounts for the poor degranulation and cell migration. Pyk2−/− mice were unable to efficiently clear infection with Staphylococcus aureus in a skin abscess model, owing in part to the poor release of granule contents at the site of infection. However, Pyk2-deficient PMNs responded normally to soluble agonists, demonstrating that this kinase functions mainly in the integrin pathway. These data demonstrate the unrealized physiologic role of this kinase in regulating the adhesion-mediated release of PMN granule contents.
Postselection Thymocyte Maturation and Emigration Are Independent of IL-7 and ERK5
Authors: Weinreich Michael A. , Jameson Stephen C. , Hogquist Kristin A.
Published: December 2010

The transcription factor Krüppel-like factor 2 (KLF2) controls the emigration of conventional T cells from the thymus through its regulation of the cell surface receptor S1P1. Prior to KLF2 expression, developing T cells require a positive selection signal through the TCR. However, following positive selection there are time, spatial, and maturational events that occur before KLF2 is finally upregulated and emigration occurs. We are interested in determining the signals that upregulate KLF2 and allow thymocytes to emigrate into circulation and whether they are linked to functional maturation. In endothelial cells KLF2 expression has been shown to be dependent on the mitogen-activated protein kinase ERK5. Furthermore, it has been reported that IL-7 signaling leads to the phosphorylation of ERK5. Thus, we hypothesized that IL-7R signaling through ERK5 could drive the expression of KLF2. In this study, we provide evidence that this hypothesis is incorrect. We also found that CD8 lineage specification occurred normally in the absence of IL-7R signaling, in contrast to a recently proposed model. We showed that both CD4 and CD8 T cells complete maturation and express KLF2 independently of ERK5 and IL-7.
Langerin+ Dermal Dendritic Cells Are Critical for CD8+ T Cell Activation and IgH γ-1 Class Switching in Response to Gene Gun Vaccines
Authors: Stoecklinger Angelika , Eticha Tekalign D. , Mesdaghi Mehrnaz , Kissenpfennig Adrien , Malissen Bernard , Thalhamer Josef , Hammerl Peter
Published: December 2010

The C-type lectin langerin/CD207 was originally discovered as a specific marker for epidermal Langerhans cells (LC). Recently, additional and distinct subsets of langerin+ dendritic cells (DC) have been identified in lymph nodes and peripheral tissues of mice. Although the role of LC for immune activation or modulation is now being discussed controversially, other langerin+ DC appear crucial for protective immunity in a growing set of infection and vaccination models. In knock-in mice that express the human diphtheria toxin receptor under control of the langerin promoter, injection of diphtheria toxin ablates LC for several weeks whereas other langerin+ DC subsets are replenished within just a few days. Thus, by careful timing of diphtheria toxin injections selective states of deficiency in either LC only or all langerin+ cells can be established. Taking advantage of this system, we found that, unlike selective LC deficiency, ablation of all langerin+ DC abrogated the activation of IFN-γ–producing and cytolytic CD8+ T cells after gene gun vaccination. Moreover, we identified migratory langerin+ dermal DC as the subset that directly activated CD8+ T cells in lymph nodes. Langerin+ DC were also critical for IgG1 but not IgG2a Ab induction, suggesting differential polarization of CD4+ T helper cells by langerin+ or langerin-negative DC, respectively. In contrast, protein vaccines administered with various adjuvants induced IgG1 independently of langerin+ DC. Taken together, these findings reflect a highly specialized division of labor between different DC subsets both with respect to Ag encounter as well as downstream processes of immune activation.
Gene Expression Patterns of Th2 Inflammation and Intercellular Communication in Asthmatic Airways
Authors: Choy David F. , Modrek Barmak , Abbas Alexander R. , Kummerfeld Sarah , Clark Hilary F. , Wu Lawren C. , Fedorowicz Grazyna , Modrusan Zora , Fahy John V. , Woodruff Prescott G. , Arron Joseph R.
Published: December 2010

Asthma is canonically thought of as a disorder of excessive Th2-driven inflammation in the airway, although recent studies have described heterogeneity with respect to asthma pathophysiology. We have previously described distinct phenotypes of asthma based on the presence or absence of a three-gene “Th2 signature” in bronchial epithelium, which differ in terms of eosinophilic inflammation, mucin composition, subepithelial fibrosis, and corticosteroid responsiveness. In the present analysis, we sought to describe Th2 inflammation in human asthmatic airways quantitatively with respect to known mediators of inflammation and intercellular communication. Using whole-genome microarray and quantitative real-time PCR analysis of endobronchial biopsies from 27 mild-to-moderate asthmatics and 13 healthy controls with associated clinical and demographic data, we found that asthmatic Th2 inflammation is expressed over a variable continuum, correlating significantly with local and systemic measures of allergy and eosinophilia. We evaluated a composite metric describing 79 coexpressed genes associated with Th2 inflammation against the biological space comprising cytokines, chemokines, and growth factors, identifying distinctive patterns of inflammatory mediators as well as Wnt, TGF-β, and platelet-derived growth factor family members. This integrated description of the factors regulating inflammation, cell migration, and tissue remodeling in asthmatic airways has important consequences for the pathophysiological and clinical impacts of emerging asthma therapeutics targeting Th2 inflammation.
Spontaneous Pregnancy Loss Mediated by Abnormal Maternal Inflammation in Rats Is Linked to Deficient Uteroplacental Perfusion
Authors: Renaud Stephen J. , Cotechini Tiziana , Quirt Jill S. , Macdonald-Goodfellow Shannyn K. , Othman Maha , Graham Charles H.
Published: December 2010

Abnormal maternal inflammation during pregnancy is associated with spontaneous pregnancy loss and intrauterine fetal growth restriction. However, the mechanisms responsible for these pregnancy outcomes are not well understood. In this study, we used a rat model to demonstrate that pregnancy loss resulting from aberrant maternal inflammation is closely linked to deficient placental perfusion. Administration of LPS to pregnant Wistar rats on gestational day 14.5, to induce maternal inflammation, caused fetal loss in a dose-dependent manner 3–4 h later, and surviving fetuses were significantly growth restricted. Pregnancy loss was associated with coagulopathy, structural abnormalities in the uteroplacental vasculature, decreased placental blood flow, and placental and fetal hypoxia within 3 h of LPS administration. This impairment in uteroplacental hemodynamics in LPS-treated rats was linked to increased uterine artery resistance and reduced spiral arteriole flow velocity. Pregnancy loss induced by LPS was prevented by maternal administration of the immunoregulatory cytokine IL-10 or by blocking TNF-α activity after treatment with etanercept (Enbrel). These results indicate that alterations in placental perfusion are responsible for fetal morbidities associated with aberrant maternal inflammation and support a rationale for investigating a potential use of immunomodulatory agents in the prevention of spontaneous pregnancy loss.
RIG-I/MDA5/MAVS Are Required To Signal a Protective IFN Response in Rotavirus-Infected Intestinal Epithelium
Authors: Broquet Alexis H. , Hirata Yoshihiro , McAllister Christopher S. , Kagnoff Martin F.
Published: December 2010

Rotavirus is a dsRNA virus that infects epithelial cells that line the surface of the small intestine. It causes severe diarrheal illness in children and ∼500,000 deaths per year worldwide. We studied the mechanisms by which intestinal epithelial cells (IECs) sense rotavirus infection and signal IFN-β production, and investigated the importance of IFN-β production by IECs for controlling rotavirus production by intestinal epithelium and virus excretion in the feces. In contrast with most RNA viruses, which interact with either retinoic acid-inducible gene I (RIG-I) or melanoma differentiation-associated gene 5 (MDA5) inside cells, rotavirus was sensed by both RIG-I and MDA5, alone and in combination. Rotavirus did not signal IFN-β through either of the dsRNA sensors TLR3 or dsRNA-activated protein kinase (PKR). Silencing RIG-I or MDA5, or their common adaptor protein mitochondrial antiviral signaling protein (MAVS), significantly decreased IFN-β production and increased rotavirus titers in infected IECs. Overexpression of laboratory of genetics and physiology 2, a RIG-I–like receptor that interacts with viral RNA but lacks the caspase activation and recruitment domains required for signaling through MAVS, significantly decreased IFN-β production and increased rotavirus titers in infected IECs. Rotavirus-infected mice lacking MAVS, but not those lacking TLR3, TRIF, or PKR, produced significantly less IFN-β and increased amounts of virus in the intestinal epithelium, and shed increased quantities of virus in the feces. We conclude that RIG-I or MDA5 signaling through MAVS is required for the activation of IFN-β production by rotavirus-infected IECs and has a functionally important role in determining the magnitude of rotavirus replication in the intestinal epithelium.
Daratumumab, a Novel Therapeutic Human CD38 Monoclonal Antibody, Induces Killing of Multiple Myeloma and Other Hematological Tumors
Authors: de Weers Michel , Tai Yu-Tzu , van der Veer Michael S. , Bakker Joost M. , Vink Tom , Jacobs Daniëlle C. H. , Oomen Lukas A. , Peipp Matthias , Valerius Thomas , Slootstra Jerry W. , Mutis Tuna , Bleeker Wim K. , Anderson Kenneth C. , Lokhorst Henk M. , van de Winkel Jan G. J. , Parren Paul W. H. I.
Published: December 2010

CD38, a type II transmembrane glycoprotein highly expressed in hematological malignancies including multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. In this study, we describe the cytotoxic mechanisms of action of daratumumab, a novel, high-affinity, therapeutic human mAb against a unique CD38 epitope. Daratumumab induced potent Ab-dependent cellular cytotoxicity in CD38-expressing lymphoma- and MM-derived cell lines as well as in patient MM cells, both with autologous and allogeneic effector cells. Daratumumab stood out from other CD38 mAbs in its strong ability to induce complement-dependent cytotoxicity in patient MM cells. Importantly, daratumumab-induced Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not affected by the presence of bone marrow stromal cells, indicating that daratumumab can effectively kill MM tumor cells in a tumor-preserving bone marrow microenvironment. In vivo, daratumumab was highly active and interrupted xenograft tumor growth at low dosing. Collectively, our results show the versatility of daratumumab to effectively kill CD38-expressing tumor cells, including patient MM cells, via diverse cytotoxic mechanisms. These findings support clinical development of daratumumab for the treatment of CD38-positive MM tumors.
Functional Consequences of Natural Sequence Variation of Murine Cytomegalovirus m157 for Ly49 Receptor Specificity and NK Cell Activation
Authors: Corbett Alexandra J. , Coudert Jerome D. , Forbes Catherine A. , Scalzo Anthony A.
Published: December 2010

The Ly49H activating receptor on C57BL/6 (B6) NK cells plays a key role in early resistance to murine cytomegalovirus (MCMV) infection through specific recognition of the MCMV-encoded MHC class I-like molecule m157 expressed on infected cells. The m157 molecule is also recognized by the Ly49I inhibitory receptor from the 129/J mouse strain. The m157 gene is highly sequence variable among MCMV isolates, with many m157 variants unable to bind Ly49HB6. In this study, we have sought to define if m157 variability leads to a wider spectrum of interactions with other Ly49 molecules and if this modifies host susceptibility to MCMV. We have identified novel m157–Ly49 receptor interactions, involving Ly49C inhibitory receptors from B6, BALB/c, and NZB mice, as well as the Ly49HNZB activation receptor. Using an MCMV recombinant virus in which m157K181 was replaced with m157G1F, which interacts with both Ly49HB6 and Ly49CB6, we show that the m157G1F–Ly49C interactions cause no apparent attenuating effect on viral clearance in B6 mice. Hence, when m157 can bind both inhibitory and activation NK cell receptors, the outcome is still activation. Thus, these data indicate that whereas m157 variants predominately interact with inhibitory Ly49 receptors, these interactions do not profoundly interfere with early NK cell responses.
Controlling Herpes Simplex Virus-Induced Ocular Inflammatory Lesions with the Lipid-Derived Mediator Resolvin E1
Authors: Rajasagi Naveen K. , Reddy Pradeep B. J. , Suryawanshi Amol , Mulik Sachin , Gjorstrup Per , Rouse Barry T.
Published: December 2010

Stromal keratitis (SK) is a chronic immunopathological lesion of the eye caused by HSV-1 infection and a common cause of blindness in humans. The inflammatory lesions are primarily perpetuated by neutrophils with the active participation of CD4+ T cells. Therefore, targeting these immune cell types represents a potentially valuable form of therapy to reduce the severity of disease. Resolvin E1 (RvE1), an endogenous lipid mediator, was shown to promote resolution in several inflammatory disease models. In the current report, we determined whether RvE1 administration begun at different times after ocular infection of mice with HSV could influence the severity of SK lesions. Treatment with RvE1 significantly reduced the extent of angiogenesis and SK lesions that occurred. RvE1-treated mice had fewer numbers of inflammatory cells that included Th1 and Th17 cells as well as neutrophils in the cornea. The mechanisms by which RvE1 acts appear to be multiple. These included reducing the influx of neutrophils and pathogenic CD4+ T cells, increasing production of the anti-inflammatory cytokine IL-10, and inhibitory effects on the production of proinflammatory mediators and molecules, such as IL-6, IFN-γ, IL-17, KC, VEGF-A, MMP-2, and MMP-9, that are involved in corneal neovascularization and SK pathogenesis. These findings are, to our knowledge, the first to show that RvE1 treatment could represent a novel approach to control lesion severity in a virally induced immunopathological disease.
Genotype–phenotype correlations of pheochromocytoma in two large von Hippel–Lindau (VHL) type 2A kindreds with different missense mutations
Authors: Nielsen Sarah M. , Rubinstein Wendy S. , Thull Darcy L. , Armstrong Michaele J. , Feingold Eleanor , Stang Michael T. , Gnarra James R. , Carty Sally E.
Published: December 2010

Von Hippel–Lindau (VHL) disease type 2A is an inherited tumor syndrome characterized by predisposition to pheochromocytoma (pheo), retinal hemangioma (RA), and central nervous system hemangioblastoma (HB). Specific VHL subtypes display genotype–phenotype correlations but, unlike other familial syndromes such as MEN‐2, the phenotype in VHL has not yet been stratified at the codon level. Over decades, we have managed two very large VHL type 2A regional kindreds with nearly adjacent but distinct VHL missense mutations. We determined the phenotype of Family 2 and compared the clinical and pathologic parameters of pheo between 30 members of Family 1 (Y112H mutation) and 33 members of Family 2 (Y98H mutation) with mean follow‐up of 15.5 and 12.1 years, respectively (P = 0.24). In Family 2, pheo was the most frequent VHL manifestation (79%) and all pheo diagnoses occurred by age 50. Age at first diagnosis was younger in Family 2 than in Family 1 (mean 19.7 vs. 28.8 years; P = 0.02). Pheo expressivity differed by genotype: Family 1 pheo was more likely to be multifocal (P = 0.04), as well as malignant (P < 0.01) and lethal (P = 0.02). Family 1 pheo was also more likely to secrete vanillylmandelic acid (VMA) alone (P = 0.05). This analysis of 130 pheochromocytomas in 63 VHL type 2A patients demonstrates that mutation‐specific malignancy and expression patterns exist within the VHL type 2A subtype, and provides information that may help tailor the screening and management algorithms of affected members and those at risk. © 2010 Wiley‐Liss, Inc.
Association of a p.Pro786Leu variant in COL2A1 with mild spondyloepiphyseal dysplasia congenita in a three‐generation family
Authors: Mark Paul R. , Torres‐Martinez Wilfredo , Lachman Ralph S. , Weaver David D.
Published: December 2010

Heterozygous sequence variants of the COL2A1 gene cause a phenotypic spectrum collectively called type II collagenopathies. Here, we describe a COL2A1 sequence variant, c.2957C>T, p.Pro986Leu in the triple helical domain, which is a Y‐position substitution in exon 41 of the repeating triplet sequence Gly‐X‐Y of the proα1(II) chain. This sequence variant was associated with a mild spondyloepiphyseal dysplasia phenotype in three individuals in a three‐generation family. On clinical examination at the age of 19 months, the proband had a flat face, bifid uvula, and a protruding abdomen. Radiographically, he had rhizomelia, mesomelia, and ovoid‐shaped vertebrae. He also had absent mineralization of the epiphyses, the os pubis, tali, and calcanei. His mother had myopia, mild lumbar lordosis, and mild coxa vara. She had a detached retina repaired at age 24 years. The maternal grandmother had cataracts but has had no kyphoscoliosis or lordosis. All three had disproportionate short stature. None had arthritis or hearing loss. The sequence variant in this family is the only reported Y‐position proline substitution in the triple helical domain (Gly‐X‐Y) of the proα1(II) coded by the COL2A1 gene. © 2010 Wiley‐Liss, Inc.
Implications of prenatal diagnosis of the fetus with both interstitial deletion and a small marker ring originating from chromosome 5
Authors: Ohashi Hiroyasu , Suzumori Kaoru , Chisaka Yasushi , Sonta Shinichi , Kobayashi Tomoko , Aoki Yoko , Matsubara Yoichi , Sone Michiko , Shaffer Lisa G.
Published: December 2010

We describe a patient with 47,XY,del(5)(p11p13), +mar observed in prenatal screening. We performed analyses including G‐banding, multi‐color fluorescent in situ hybridization (mFISH) for fetal chromosome detection. After birth array‐based comparative genomic hybridization (aCGH), bacterial artificial chromosome (BAC)‐FISH was carried out to define the chromosomal changes precisely. The mFISH revealed that a ring chromosome that had originated from chromosome 5. The aCGH showed that this fetus had a terminal duplication, an interstitial deletion, and a pericentromeric duplication of the short arm of chromosome 5. This complex alteration resulted in partial trisomy 5p15.33–p15.31, partial monosomy 5p14.3–p13.2, and partial trisomy 5p12–p11. To clarify these alterations, we performed BAC‐FISH using BAC clones related to deleted and duplicated regions, and found that a derivative (der) chromosome 5 showed the presence of hybridization signals from the duplicated region at 5p15.33 and the loss of hybridization signals from the deleted region at 5p14.2. In addition, FISH analysis confirmed the origin of the marker chromosome. Hybridization signals from the second intervening sequence at 5p13.1, between the deleted region and the pericentric duplicated region, were present on the marker ring chromosome. © 2010 Wiley‐Liss, Inc.
Thanatophoric dysplasia type II with encephalocele and semilobar holoprosencephaly: Insights into its pathogenesis
Authors: Martínez‐Frías M.L. , Egüés X. , Puras A. , Hualde J. , de Frutos C.A. , Bermejo E. , Nieto M.A. , Martínez S.
Published: December 2010

Thanatophoric dysplasia (TD) is a lethal form of short‐limb skeletal dysplasia that is associated with macrocephaly, and variably cloverleaf skull. Two types of TD are clinically recognized, TD1 and TD2, mainly distinguished by their radiographic characteristics. The differences between the two are principally observed in the femur, which appears curved in TD1, while it remains straight but with a proximal medial spike in TD2, and are a less severe overall affectation in TD2. Both types of TD are caused by mutations in different functional domains of the FGFR3 gene. However, whereas several mutations in the different domains of FGFR3 cause TD1, the K650E mutation involving the change of a lysine to glutamic acid (“Lys650Glu”) has been found in all TD2 cases to date. Here we describe a newborn infant with TD2 associated with brain defects that have either been infrequently observed (encephalocele) or not hitherto described (holoprosencephaly). Based on recent studies, we consider encephaloceles described in TD to be pseudoencephaloceles, since they are secondary to the intracranial pressure generated by severe hydrocephaly and to severe cranial structural anomalies. Finally, to analyze the mechanisms of holoprosencephaly observed in the case described here, we include a concise review on the current understanding of how FGFs and their receptors are expressed in the rostral signaling center (particularly Fgf8). In addition, we evaluated recent observations that FGF ligands and receptors (including FGFR3) act in concert to organize the whole telencephalon activity, rather than independently patterning different areas. © 2010 Wiley‐Liss, Inc.
Are MPS II heterozygotes actually asymptomatic? A study based on clinical and biochemical data, X‐inactivation analysis and imaging evaluations
Authors: de Camargo Pinto Louise Lapagesse , Maluf Sharbel Weidner , Leistner‐Segal Sandra , Zimmer da Silva Camila , Brusius‐Facchin Ana , Burin Maira Graef , Brustolin Silvia , Llerena Juan , Moraes Lucia , Vedolin Leonardo , Schuch Alice , Giugliani Roberto , Schwartz Ida Vanessa Doederlein
Published: December 2010

For some X‐linked disorders the expressivity and penetrance in females are almost similar to those ones found in males. For mucopolysaccharidosis type II (MPS II), there are no studies in the literature trying to identify subtle signs and symptoms of this disease in heterozygotes. The objective of this study was to compare heterozygotes and non‐heterozygotes for MPS II, in order to test the hypothesis that heterozygotes may present subtle manifestations of the disease. In this observational and transversal study we collected data on 40 Brazilian women with a positive familial history for MPS II that included clinical and physical exam, karyotype, pattern of X‐inactivation, iduronate‐2‐sulfatase (IDS) activity in leukocytes and plasma, urinary glycosaminoglycans levels, computerized tomography scans (CT) of abdomen and spine, and brain magnetic resonance imaging. The Results showed the following: According to DNA analysis, 22 women were classified as heterozygote and 18 as non‐heterozygotes. We did not find any abnormality on physical examination, karyotype, or spine CT. Also the pattern of X‐inactivation was not different between the groups. Applying the Bonferroni's correction, both groups were found to differ only in relation to IDS activity in plasma and in leukocyte, which were lower in heterozygotes. In our investigation we did not find any evidence of subtle clinical manifestations of MPS II in heterozygotes. Our findings suggest there is no relation between the absence of clinical signs in these women and the occurrence of a favorable skewing pattern of X‐inactivation. © 2010 Wiley‐Liss, Inc.
Genetic diseases in the Tunisian population
Authors: Romdhane Lilia , Abdelhak Sonia ,   for the Research Unit on Molecular Investigation of Genetic Orphan Diseases,   and Collaborators
Published: December 2010

Tunisia is one of the North African countries, geographically situated in a central position at the crossroad between Africa and Europe. The demographic features of the Tunisian population include among others high rates of consanguinity. We report, here on the spectrum of genetic diseases in Tunisia. The review of the literature, including other available information (gray literature) showed that there are at least 346 genetic disorders for which cases have been identified in the Tunisian population. Among these, 62.9% are autosomal recessive, 23% autosomal dominant, 5.4% X‐linked, and the remaining are of Y‐linked, mitochondrial, and unknown mode of transmission. Fifty percent of the reported conditions in this study are caused by at least one mutation. For autosomal recessive diseases, most of the mutations were identified at homozygous state among the affected individuals. Part of the mutations was the result of a founder effect; these are the consequences of the high rate of consanguinity. The congenital malformations, diseases of the nervous system and metabolic disorders are the major groups of genetic diseases affecting the Tunisian population. The large spectrum of diseases and their relatively high frequency could be explained by the high degree of inbreeding and the presence of multiple mutations, either allelic or in different genes. This is due to the richness of the genetic background of the studied population. A multidisciplinary approach is essential to develop adequate preventive programmes adapted to the social, cultural, and economic context. © 2010 Wiley‐Liss, Inc.
Incidence and natural history of mucopolysaccharidosis type III in France and comparison with United Kingdom and Greece
Authors: Héron Bénédicte , Mikaeloff Yann , Froissart Roseline , Caridade Guillaume , Maire Irène , Caillaud Catherine , Levade Thierry , Chabrol Brigitte , Feillet François , Ogier Hélène , Valayannopoulos Vassili , Michelakakis Helen , Zafeiriou Dimitrios , Lavery Lucy , Wraith Ed , Danos Olivier , Heard Jean‐Michel , Tardieu Marc
Published: December 2010

Sanfilippo syndrome, or mucopolysaccharidosis type III (MPSIII) is a lysosomal storage disease with predominant neurological manifestations in affected children. It is considered heterogeneous with respect to prevalence, clinical presentation, biochemistry (four biochemical forms of the disease referred to as MPSIIIA, B, C, and D are known), and causative mutations. The perspective of therapeutic options emphasizes the need for better knowledge of MPSIII incidence and natural history. We performed parallel retrospective epidemiological studies of patients diagnosed with MSPIII in France (n = 128), UK (n = 126), and Greece (n = 20) from 1990 to 2006. Incidences ranged from 0.68 per 100,000 live‐births in France to 1.21 per 100,000 live‐births in UK. MPSIIIA, which predominates in France and UK, was absent in Greece, where most patients have MPSIIIB. The study confirmed the large allelic heterogeneity of MPSIIIA and MPSIIIB and detected several yet undescribed mutations. Analysis of clinical manifestations at diagnosis and over a 6–7 years follow‐up indicated that almost all patients, whatever the disease subtype, expressed neurological manifestations before the age of 5 years, including language acquisition delay, cognitive delay, and/or abnormal behavior. In contrast to relatively homogeneous early onset manifestations, disease progression showed significant variation depending on subtype and age at diagnosis. Different severities of disease progressions and different allele distribution between France and UK suggested that mutations are not equally deleterious, although genotype–phenotype correlation could not be established. Notwithstanding the rapidity of further clinical deterioration, all MPSIII patients suffer early onset devastating neurological manifestations that deserve early treatment when available. © 2010 Wiley‐Liss, Inc.