bluuebunny/crossref_metadata_2025 huggingface dataset:
Back to the Suture: The Distribution of Intraspecific Genetic Diversity in and Around Anatolia
Authors: Bilgin Rasit
Published: June 2011

The effect of ice ages in speciation and diversification is well established in the literature. In Europe, the Iberian, the Italian and the Balkan peninsulas comprise the main glacial refugia, where the subsequent re-population of Europe started. Though not studied as extensively, Anatolia has also been hinted to be a potential glacial refugium for Europe, and with its proximity to the Caucasus and the Middle East at the same time, has potential to exhibit high levels of intraspecific diversity. The more ubiquitous use and cheaper availability of molecular methods globally now makes it possible to better understand molecular ecology and evolution of the fauna and flora in the genetically understudied regions of the world, such as Anatolia. In this review, the molecular genetic studies undertaken in Anatolia in the last decade, for 29 species of plants and animals, are examined to determine general phylogeographic patterns. In this regard, two major patterns are observed and defined, showing genetic breaks within Anatolia and between Anatolia and the Balkans. A third pattern is also outlined, which suggests Anatolia may be a center of diversity for the surrounding regions. The patterns observed are discussed in terms of their relevance to the location of suture zones, postglacial expansion scenarios, the effect of geographic barriers to gene flow and divergence time estimates, in order to better understand the effect of the geological history of Anatolia on the evolutionary history of the inhabitant species. In view of the current state of knowledge delineated in the review, future research directions are suggested.
Novel Polymorphic Microsatellite Loci for the Korean Black Scraper (Thamnaconus modestus), and Their Application to the Genetic Characterization of Wild and Farmed Populations
Authors: An Hye Suck , Kim Eun Mi , Lee Jang Wook , Dong Chun Mae , Lee Bai Ik , Kim Yi Cheong
Published: June 2011

In this study, we developed 20 polymorphic microsatellite markers for the Korean black scraper, Thamnaconus modestus (Günther, 1877), Monacanthidae, and used them to compare allelic variation between wild and hatchery populations in Korea. All loci were readily amplified and demonstrated allelic variability, with the number of alleles ranging from 5–35 in the wild population and 5–22 in the farmed population. The average observed and expected heterozygosities were estimated, respectively, as 0.74 and 0.80 in the hatchery samples and 0.78 and 0.81 in the wild ones. These results indicate lower genetic variability in the hatchery population than in the wild population and minor, but significant, genetic differentiation between the two populations (FST = 0.005, P < 0.01). Additionally, cross-amplification was tested in another monacanthid species, Stephanolepis cirrhifer; many loci were found that yielded useful information. The high degree of polymorphism exhibited by the 20 microsatellites will be useful in future aquaculture and population genetic studies for developing conservation and management plans.
Multi-Composite Bioactive Osteogenic Sponges Featuring Mesenchymal Stem Cells, Platelet-Rich Plasma, Nanoporous Silicon Enclosures, and Peptide Amphiphiles for Rapid Bone Regeneration
Authors: Murphy Matthew  B. , Blashki Daniel , Buchanan Rachel  M. , Fan Dongmei , De Rosa Enrica , Shah Ramille  N. , Stupp Samuel I. , Weiner Bradley  K. , Simmons Paul  J. , Ferrari Mauro , Tasciotti Ennio
Published: June 2011

A novel bioactive sponge was created with a composite of type I collagen sponges or porous poly(e-caprolactone) (PCL) scaffolds, platelet-rich plasma (PRP), BMP2-loaded nanoporous silicon enclosure (NSE) microparticles, mineralizing peptide amphiphiles (PA), and mesenchymal stem cells (MSC). Primary MSC from cortical bone (CB) tissue proved to form more and larger colony units, as well as produce more mineral matrix under osteogenic differentiation, than MSC from bone marrow (BM). Coating pre-treatments were optimized for maximum cell adhesion and mineralization, while a PRP-based gel carrier was created to efficiently deliver and retain MSC and microparticles within a porous scaffold while simultaneously promoting cell recruitment, proliferation, and angiogenesis. Components and composite sponges were evaluated for osteogenic differentiation in vitro. Osteogenic sponges were loaded with MSC, PRP, PA, and NSE and implanted subcutaneously in rats to evaluate the formation of bone tissue and angiogenesis in vivo. It was found that the combination of a collagen sponge with CB MSC, PRP, PA, and the BMP2-releasing NSE formed the most bone and was most vascularized by four weeks compared to analogous composites featuring BM MSC or PCL or lacking PRP, PA, and NSE. This study indicates that CB MSC should be considered as an alternative to marrow as a source of stem cells, while the PRP-PA cell and microparticle delivery system may be utilized for diverse tissue engineering applications.
Synthetic Dye - Inorganic Salt Hybrid Colorants for Application in Thermoplastics
Authors: Wei Yan-Ping , Li Tian , Gao Hong-Wen
Published: June 2011

Common synthetic dyes, e.g., Weak Acid Pink Red B (APRB, C.I. 18073), Mordant Blue 9 (MB, C.I.14855) and Acid Brilliant Blue 6B (ABB6B, C.I. 42660), can be removed from water by in situ hybridization with CaCO3, BaSO4 and Ca3(PO4)2 and the resulting hybrids thus prepared used as plastic colorants. All the hybrids can be processed into polypropylene (PP) at 200 °C with good color intensity, color brightness and homogeneous dispersion. The BaSO4-MB hybrid exhibits better migration resistance to acid and alkali, and stronger covering power than the BaSO4-MB mixture. The thermal stability and UV resistance of the Ca3(PO4)2-ABB6B hybrid are better than those of the Ca3(PO4)2-ABB6B mixture. The crystallinity of PP is enhanced by incorporation of these hybrids and the use of these hybrids as colorants in PP instead of the dyes alone is determined to be feasible.
Reactions of Some New Thienothiophene Derivatives
Authors: Mabkhot Yahia Nasser , Al-Majid Abdullah Mohammad , Alamary Abdullah Saleh , Warad Ismail , Sedigi Yamin
Published: June 2011

Facile and convenient syntheses of bisdimethylthieno[2,3-b]thiophen-2,5-diyl bis(oxazole-2-amine), bis(1H-imidazol-2-amine), bis((3a)-H-indole),[1,2-a]pyrimidine), bis(1H-imidazo[1,2-b][1,2,4]triazole) and bis(9H-benzo[d]imidazo[1,2-a]imidazole) derivatives incorporating a thieno[2,3-b]thiophene moiety from the versatile and readily accessible 1,1'(3,4-dimethylthieno[2,3-b]thiophene-2,5-diyl)-bis(2-bromo-ethanone) (1) are described.
Phytochemical Analysis and In Vitro Antimicrobial and Free-Radical-Scavenging Activities of the Essential Oils from Euryops arabicus and Laggera decurrens
Authors: Mothana Ramzi A. , Alsaid Mansour S. , Al-Musayeib Nawal M.
Published: June 2011

The essential oils of the aerial part of two Asteraceae species, namely Euryops arabicus Steud. and Laggera decurrens (Vahl.) Hepper and Wood, were studied by GC and GC/MS. In parallel the antimicrobial and antioxidant activities were evaluated. The investigation led to the identification of 48 and 44 compounds for both plants, respectively. The essential oil of E. arabicus was rich in oxygenated sesquiterpenes (39.9%). The oil also contained a high content of sesquiterpene hydrocarbons (24.1%). Compounds such as caryophyllene oxide (8.6%), T-cadinol (7.0%), spathulenol (5.2%), (E)-β-caryophyllene (6.0%) and 2-epi-(E)-β-caryophyllene (6.0%) were the main constituents of the oil. Oxygenated monoterpenes also predominated in L. decurrens (46.3%). The thymoquinone-derivative, 3-methoxy-2-methyl-5-(1-methylethyl)-2,5-cyclohexadiene-1,4-dione (28.1%), thymol (5.7%) and eudesma-11-en-4a-ol (7.0%) were the most abundant constituents. Both essential oils showed antimicrobial activity with MIC-values between 0.13–5.25 mg/mL. Furthermore, only the essential oil of L. decurrens exhibited a strong antioxidant activity (91%) at 500 µg/mL.
A Role for Sigma Receptors in Stimulant Self Administration and Addiction
Authors: Katz Jonathan L. , Su Tsung-Ping , Hiranita Takato , Hayashi Teruo , Tanda Gianluigi , Kopajtic Theresa , Tsai Shang-Yi
Published: June 2011

Sigma1 receptors (σ1Rs) represent a structurally unique class of intracellular proteins that function as chaperones. σ1Rs translocate from the mitochondria-associated membrane to the cell nucleus or cell membrane, and through protein-protein interactions influence several targets, including ion channels, G-protein-coupled receptors, lipids, and other signaling proteins. Several studies have demonstrated that σR antagonists block stimulant-induced behavioral effects, including ambulatory activity, sensitization, and acute toxicities. Curiously, the effects of stimulants have been blocked by σR antagonists tested under place-conditioning but not self-administration procedures, indicating fundamental differences in the mechanisms underlying these two effects. The self administration of σR agonists has been found in subjects previously trained to self administer cocaine. The reinforcing effects of the σR agonists were blocked by σR antagonists. Additionally, σR agonists were found to increase dopamine concentrations in the nucleus accumbens shell, a brain region considered important for the reinforcing effects of abused drugs. Although the effects of the σR agonist, DTG, on dopamine were obtained at doses that approximated those that maintained self administration behavior those of another agonist, PRE-084 required higher doses. The effects of DTG were antagonized by non-selective or a preferential σ2R antagonist but not by a preferential σ1R antagonist. The effects of PRE-084 on dopamine were insensitive to σR antagonists. The data suggest that the self administration of σR agonists is independent of dopamine and the findings are discussed in light of a hypothesis that cocaine has both intracellular actions mediated by σRs, as well as extracellular actions mediated through conventionally studied mechanisms. The co-activation and potential interactions among these mechanisms, in particular those involving the intracellular chaperone σRs, may lead to the pernicious addictive effects of stimulant drugs.
Control of Aflatoxin Production of Aspergillus flavus and Aspergillus parasiticus Using RNA Silencing Technology by Targeting aflD (nor-1) Gene
Authors: Abdel-Hadi Ahmed M. , Caley Daniel P. , Carter David R. F. , Magan Naresh
Published: June 2011

Aspergillus ﬂavus and Aspergillus parasiticus are important pathogens of cotton, corn, peanuts and other oil-seed crops, producing toxins both in the field and during storage. We have designed three siRNA sequences (Nor-Ia, Nor-Ib, Nor-Ic) to target the mRNA sequence of the aflD gene to examine the potential for using RNA silencing technology to control aflatoxin production. Thus, the effect of siRNAs targeting of two key genes in the aflatoxin biosynthetic pathway, aflD (structural) and aflR (regulatory gene) and on aflatoxin B1 (AFB1), and aflatoxin G1 (AFG1) production was examined. The study showed that Nor-Ib gave a significant decrease in aflD mRNA, aflR mRNA abundance, and AFB1 production (98, 97 and 97% when compared to the controls) in A. flavus NRRL3357, respectively. Reduction in aflD and aflR mRNA abundance and AFB1 production increased with concentration of siRNA tested. There was a significant inhibition in aflD and AFB1 production by A. flavus EGP9 and AFG1 production by A. parasiticus NRRL 13005. However, there was no significant decrease in AFG1 production by A. parasiticus SSWT 2999. Changes in AFB1 production in relation to mRNA levels of aflD showed a good correlation (R = 0.88; P = 0.00001); changes in aflR mRNA level in relation to mRNA level of aflD also showed good correlation (R = 0.82; P = 0.0001). The correlations between changes in aflR and aflD gene expression suggests a strong relationship between these structural and regulatory genes, and that aflD could be used as a target gene to develop efficient means for aflatoxin control using RNA silencing technology.
Loss of vtx Genes after the First Subcultivation Step of Verocytotoxigenic Escherichia coli O157 and Non-O157 during Isolation from Naturally Contaminated Fecal Samples
Authors: Joris Maria-Adelheid , Verstraete Karen , De Reu Koen , De Zutter Lieven
Published: June 2011

Verocytotoxins VT1 and VT2, produced by Verocytotoxigenic Escherichia coli (VTEC), are encoded on temperate bacteriophages. Several studies reported the loss of the vtx genes after multiple subcultivation steps or long preservation. The objective of this study was to determine if the loss of the verocytotoxin genes can already occur during the first subcultivation step. Consequently, the stability of the vtx genes were tested in 40 isolates originating from 40 vtx-positive fecal samples after the first subcultivation step following the isolation procedure. The loss occurred in 12 out of 40 strains tested and was rather rare among the O157 strains compared to the non-O157 strains. This is the first study demonstrating that the loss of the verocytotoxin genes can already occur after the first subcultivation step. This may lead to an underestimation of VTEC positive samples.
Care Partnerships Between Family Physicians and Rheumatologists
Authors: LOU BENJAMIN , DE CIVITA MIRELLA , EHRMANN FELDMAN DEBBIE , BISSONAUTH ASVINA , BERNATSKY SASHA
Published: June 2011

Objective.

To describe care partnerships between family physicians and rheumatologists.

Methods.

A random sample (20%, n = 478) of family physicians was mailed a questionnaire, asking if there was at least 1 particular rheumatologist to whom the physician tended to refer patients. If the answer was affirmative, the physician would be considered as having a “care partnership” with that rheumatologist. The family physician then rated, on a 5-point scale, factors of importance regarding the relationship with that rheumatologist.

Results.

The questionnaire was completed by 84/462 (18.2%) of family physicians; 52/84 (61.9%) reported having rheumatology care partnerships according to our definition. Regarding interactions with rheumatologists, most respondents rated the following as important (score ≥ 4): adequate communication and information exchange (44/50, 88.0%); waiting time for new patients (40/50, 80.0%); clear and appropriate balance of responsibilities (39/49, 79.6%); and patient feedback and preferences (34/50, 68%). Male family physicians were more likely than females to accord high importance to personal knowledge of the rheumatologist, and to physical proximity of the rheumatologist’s practice. Regarding relationships with rheumatologists, 30/50 (60.0%) of respondents felt communication and information exchange were adequate, and 35/50 (70.0%) felt they had a clear balance of responsibilities.

Conclusion.

Almost two-thirds of family physicians have rheumatology care partnerships, according to our definition. In this partnership, establishing adequate communication and shorter waiting time seem of paramount importance to family physicians. A balanced sharing of responsibilities and patients’ preferences are also valued. Although many physicians reported adequate communication and clear and appropriate balance of responsibilities in their current interactions with rheumatologists, there appears to be room for improvement.
The Effect of Osteoarthritis of the Hip or Knee on Work Participation
Authors: BIELEMAN HENDRIK J. , BIERMA-ZEINSTRA SITA M.A. , OOSTERVELD FRITS G.J. , RENEMAN MICHIEL F. , VERHAGEN ARIANNE P. , GROOTHOFF JOHAN W.
Published: June 2011

In our systematic literature search, we included studies involving patients with hip or knee osteoarthritis (OA) and outcome measures of work participation. Methodological quality was assessed using 11 criteria; a qualitative data analysis was performed. Fifty-three full-text articles were selected out of 1861 abstracts; finally, data were extracted from 14 articles. Design, populations, definitions, and measurements in the studies showed large variations; work outcomes were often only secondary objectives. The outcomes were summarized as showing a mild negative effect of OA on work participation. Many patients had paid work and managed to stay at work despite limitations. However, research on the effect of OA on work participation is scarce and the methodological quality is often insufficient. The longitudinal course of work participation in individuals with OA has not been described completely.
Bone Health in Adult Men and Women with a History of Juvenile Idiopathic Arthritis
Authors: THORNTON JUDITH , PYE STEPHEN R. , O’NEILL TERENCE W. , RAWLINGS DAVID , FRANCIS ROGER M. , SYMMONS DEBORAH P.M. , ASHCROFT DARREN M. , FOSTER HELEN E.
Published: June 2011

Objective.

Our aim was to determine areal bone mineral density (BMDa) and disease-related factors linked with BMDa in adults with a history of juvenile idiopathic arthritis (JIA).

Methods.

Men and women with a history of JIA attending a young adult rheumatology clinic in Newcastle, UK, underwent dual energy x-ray absorptiometry (DEXA) of the lumbar spine and total hip. Information was obtained about disease duration and subtype, previous treatment including corticosteroid and methotrexate therapy, and large-joint replacement. Subjects completed the modified Health Assessment Questionnaire (HAQ). Blood was taken for assessment of C-reactive protein, erythrocyte sedimentation rate, and rheumatoid factor (RF).

Results.

Seventy-one women and 16 men, mean age 28.7 and 31.4 years, and mean disease duration 20.6 and 24.0 years, respectively, were studied. Mean BMDa was 0.982 (Z-score = −0.328; 95% CI −0.657, 0.001) and 1.028 g/cm2 (Z-score = −0.251; 95% CI −1.266, 0.764) in women and men, respectively, at the spine and 0.817 (Z-score = −0.542; 95% CI −0.975, −0.109) and 0.857 g/cm2 (Z-score = −0.176; 95% CI −2.323, 1.971) at the hip. After adjusting for age and sex, increasing HAQ score was associated with both lower spine BMDa and hip BMDa. Compared with patients with oligoarticular disease, those with enthesitis-related arthritis had higher BMDa at the spine, while those with extended oligoarticular and polyarticular RF-negative disease had lower hip BMDa. Oral corticosteroids and the presence of a large-joint replacement were associated with lower BMDa at both the spine and hip.

Conclusion.

There was a trend toward low BMDa in women with a history of JIA. These patients may be at risk of the complications of osteoporosis including fragility fractures and should be considered for targeted preventive measures.
Effect of the Application of Trial Inclusion Criteria on the Efficacy of Adalimumab Therapy in a Rheumatoid Arthritis Cohort
Authors: VISMAN INGRID M. , BARTELDS GEERTJE M. , OUWERKERK WOUTER , RAVELLI ANITA C.J. , PEELEN LINDA M. , DIJKMANS BEN A.C. , BOERS MAARTEN , NURMOHAMED MIKE T.
Published: June 2011

Objective.

To evaluate the influence of inclusion criteria used in rheumatoid arthritis (RA) trials with adalimumab on clinical outcome and response.

Methods.

The different inclusion criteria of published trials of adalimumab in RA were separately applied to a large prospective cohort of patients with RA treated with adalimumab (AdRA cohort), thereby mimicking patient selection for a clinical trial. Clinical response and outcome in the resulting 11 projection groups were compared using the 28-joint Disease Activity Score (DAS28) and time-averaged DAS28 as outcome measures of efficacy.

Results.

Thirteen trials (n = 54–799) with 11 different sets of entry criteria were identified, resulting in 11 projection groups (n = 22–168). The DAS28 at baseline was similar in the original trial and each projection group based on this trial (5.1–6.4, total AdRA cohort 5.1). After 28 weeks, the efficacy varied substantially among the 11 projected groups (change from baseline DAS28: −1.65 to −2.65, time-averaged DAS28 3.67–4.53). Expressed as outcome (DAS28 at 28 weeks), the efficacy was much more similar for almost all projection groups (3.5–4.0) and thus appeared to be mostly independent of disease activity at baseline.

Conclusion.

We observed that different inclusion criteria for clinical trials can have a marked effect on the expected response, i.e., improvement from baseline. A novel finding is that final disease activity appeared much less dependent on initial disease activity. Our study suggests that for daily practice, one can assume that adalimumab treatment will on average result in a DAS28 between 3.5 and 4.0 after 28 weeks of treatment, regardless of baseline disease activity.
Safety and Efficacy of Rituximab in Severe Juvenile Dermatomyositis: Results from 9 Patients from the French Autoimmunity and Rituximab Registry
Authors: BADER-MEUNIER BRIGITTE , DECALUWE HÉLÈNE , BARNERIAS CHRISTINE , GHERARDI ROMAIN , QUARTIER PIERRE , FAYE ALBERT , GUIGONIS VINCENT , PAGNIER ANNE , BROCHARD KARINE , SIBILIA JEAN , GOTTENBERG JACQUES-ERIC , BODEMER CHRISTINE
Published: June 2011

Objective.

To evaluate the safety and efficacy of rituximab (RTX) in juvenile dermatomyositis (JDM) in off-trial patients.

Methods.

We conducted a multicenter prospective study of patients with JDM included in the French Autoimmunity and Rituximab (AIR) registry.

Results.

Nine patients with severe JDM were studied. The main indication for RTX treatment was severe and/or refractory muscle involvement (7 patients), severe calcinosis (1 patient), or severe chronic abdominal pain associated with abdominal lipomatosis (1 patient). RTX was associated with corticosteroids, immunosuppressive drugs, and plasma exchange therapy in 9/9, 5/9, and 2/9 patients, respectively. Mild infections of the calcinosis sites occurred in 2 patients and an infusion-related event in 1. Complete clinical response was achieved in 3/6 patients treated with RTX for muscle involvement. In these responders steroid therapy was stopped or tapered to < 15% of the baseline dosage, with no relapse, with a followup ranging from 1.3 to 3 years. Calcinosis did not improve in the 6 affected patients.

Conclusion.

This small series suggests that rituximab may be effective for treating muscle and skin involvement in a small subset of children with severe JDM, and that its safety profile was satisfactory. Further studies are needed to identify predictive factors of response to RTX in patients with severe JDM.
Opposition de gauche et opposition islamiste en Egypte : concepts et pratiques révolutionnaires partagés
Authors: Régnault Amélie
Published: June 2011

La révolte égyptienne de janvier-février 2011 a été impulsée puis menée par une coalition hétéroclite de forces sociales et politiques. Un tel rassemblement est l’aboutissement d’un processus nourri depuis les années 1970 : la constitution et le renforcement d’une opposition égyptienne, dont le spectre s’étend de la gauche « progressiste » aux Frères musulmans et qui partage des mots d’ordre largement empruntés à l’arsenal conceptuel socialiste. D’abord brandis par le régime nassérien afin de légitimer le pouvoir, les concepts anti-impérialistes sont peu à peu réappropriés par une partie de l’opposition, qui les intègre à un discours aussi bien « progressiste » qu’islamiste. Malgré son caractère hétérogène, cette dernière adopte la stratégie du rassemblement à plusieurs reprises, entre les années 1970 et 2011, pour former un front uni contre le régime. Communistes et islamistes, privés de statut légal, rivalisent pour le contrôle des espaces de mobilisation, comme les universités. Pourtant, seuls les seconds parviennent réellement à impulser ou récupérer une dynamique d’opposition soutenue par la population.
Confisquer pour redistribuer : la circulation de la grâce royale d'après l'exemple de la forfaiture de Pierre Remi (1328)
Authors: Canteaut Olivier
Published: June 2011

Résumé À l’avènement de Philippe VI, Pierre Remi, trésorier et homme de confiance de Charles IV, subit le sort de nombre de favoris royaux : tombé en disgrâce et condamné à mort suite à un procès d’exception, il fut exécuté le 25 avril 1328. Philippe VI fit ainsi du favori de son prédécesseur un bouc émissaire ; par le sacrifice de celui-ci, le nouveau souverain travailla à créer un temps d’unanimité politique destiné à régénérer la monarchie. Le souverain tira aussi un profit matériel de cette exécution, puisqu’il mit la main sur l’immense fortune que Pierre Remi avait accumulée du temps de sa splendeur. Pourtant, il s’employa aussitôt à dilapider les biens ainsi acquis et, au terme de 41 actes répartis sur huit années, il n’en conserva presque rien. Trois groupes bénéficièrent de cette redistribution : des créanciers de la monarchie, ainsi payés d’une partie de leur dû ; des conseillers et des barons du roi, récompensés par des dons de leur soutien au nouveau roi ; et des serviteurs plus modestes, souvent issus de l’hôtel royal, eux aussi remerciés par des libéralités. Que la redistribution des biens de Pierre Remi répondît à des nécessités financières et politiques ou qu’elle pût apparaître comme une dilapidation gratuite et inutile, elle permit au roi de tenir son rôle de patron auprès de ses serviteurs. Elle attesta même, à travers tout le royaume, la capacité à donner du nouveau souverain, capacité essentielle pour régner dans la mesure où le don, avec la grâce judiciaire, constitue l’un des deux fondements du gouvernement royal par la grâce. Dons et confiscations constituent deux modalités complémentaires de circulation des biens et le développement de la théorie de l’inaliénabilité du domaine royal les rend indissociables. Les favoris déchus, comme Pierre Remi, l’attestent : accumulant les dons émanant du roi, voire les monopolisant, ils s’en voient à leur chute dépossédés au profit de nouveaux bénéficiaires des largesses royales. Le souverain, tout en étant le maître de cette circulation des biens, n’en tire pas de profit matériel. Mais il y régénère régulièrement son pouvoir.
Corneal Crosslinking for Progressive Keratoconus in Four Children
Authors: Soeters Nienke , Van der Lelij Allegonda , van der Valk Rikkert , Tahzib Nayyirih G.
Published: June 2011

The authors describe four children with progressive keratoconus treated by corneal crosslinking (CXL). The current CXL guidelines recommend treatment of patients 18 years and older. Nevertheless, keratoconus can rapidly progress in young teenagers. CXL could be a safe procedure to prevent a keratoplasty at a young age.
La valoración social del despacho institucional en el primer tercio del siglo XX
Authors: Aguiló-Alonso María Paz
Published: June 2011

Documentar la labor de ebanistería en el Madrid finisecular ha permitido estudiar las condiciones sociales que en los edificios públicos implicaron el desarrollo del despacho, como elemento representativo de los distintos estadios existentes, sobre todo a nivel ministerial y cuya evolución marcará la pauta de los sistemas de amueblamiento modernos. Este estudio se realiza sobre la base documental y gráfica conservada en el Ministerio de Hacienda, sobre tres acciones coordinadas en todas las Delegaciones de Hacienda, permitiendo registrar una amplia lista de casas comerciales y talleres activos entre 1900 y 1936.
Monumentalizar la ciudad y registrarla, una contribución moderna al conocimiento
Authors: Vega Jesusa
Published: June 2011

En el cambio del siglo, del XVIII al XIX, la cámara oscura se constituyó como una máquina fundamental tanto en lo que respecta al diseño de las primeras cámaras fotográficas como en la continuidad de la manera de ver. En consecuencia, las bases para la recepción de la fotografía se establecieron en el periodo ilustrado, de modo que en el objetivo de fijar la imagen de la cámara oscura no existió ninguna ruptura. Estrechamente relacionado con la cámara oscura estaba el ‘cajón óptico’; se estableció un mercado internacional de estampas y las imágenes de mayor éxito fueron las vistas de ciudades y monumentos. Entre esas estampas se encontraban las que mostraban a España.
FOXO3 Deficiency Leads to Increased Susceptibility to Cigarette Smoke-Induced Inflammation, Airspace Enlargement, and Chronic Obstructive Pulmonary Disease
Authors: Hwang Jae-woong , Rajendrasozhan Saravanan , Yao Hongwei , Chung Sangwoon , Sundar Isaac K. , Huyck Heidie L. , Pryhuber Gloria S. , Kinnula Vuokko L. , Rahman Irfan
Published: June 2011

Forkhead box class O 3a (FOXO3) is a member of the FoxO transcription factor subfamily, which regulates the expression of target genes not only through DNA binding as a transcription factor, but also through protein–protein interaction. Although FoxO3 is a well-known transcription factor involved in diverse biological processes, the role of FoxO3 in cigarette smoke (CS)-induced lung inflammation and injury has not been studied. It is, therefore, hypothesized that deficiency of FoxO3 leads to increased susceptibility to CS-induced lung inflammatory response and airspace enlargement. In this article, we show that the levels of FOXO3 are significantly decreased in lungs of smokers and patients with chronic obstructive pulmonary disease, as well as in lungs of mice exposed to CS. Genetic ablation of FoxO3 led to pulmonary emphysema and exaggerated inflammatory response in lungs of mice exposed to CS. We further showed that CS induced the translocation of FoxO3 into the nucleus where FoxO3 interacted with NF-κB and disrupted NF-κB DNA-binding ability, leading to inhibition of its activity. Targeted disruption of FoxO3 also resulted in downregulation of antioxidant genes in mouse lungs in response to CS exposure. These results suggest that FoxO3 plays a pivotal role in regulation of lung inflammatory response and antioxidant genes, and deficiency of FoxO3 results in development of chronic obstructive pulmonary disease/emphysema.
Cecal Ligation and Puncture-Induced Impairment of Innate Immune Function Does Not Occur in the Absence of Caspase-1
Authors: Murphey E. D.
Published: June 2011

Mice that have been subjected to cecal ligation and puncture (CLP) have an impaired ability to clear a subsequent Pseudomonas aeruginosa challenge compared with that of sham CLP controls. We hypothesized that this outcome is dependent upon a caspase-1 mechanism and tested this hypothesis by measuring caspase-1 after CLP and by measuring clearance of a bacterial challenge in caspase-1–deficient mice after CLP. Wild-type mice subjected to CLP had increased caspase-1 activity as well as increased IL-1β and increased IL-18 production in splenocytes stimulated with heat-killed Pseudomonas and had increased plasma concentrations of IL-1β and IL-18 and impaired clearance of a P. aeruginosa challenge compared with sham controls. Healthy, uninjured caspase-1−\− mice did not differ from wild-type mice in their ability to clear a Pseudomonas challenge. However, unlike wild-type mice, caspase-1−/− mice subjected to CLP had no impairment of bacterial clearance of the Pseudomonas challenge, suggesting that caspase-1 induction after CLP played a role in impairment of bacterial clearance. This was further substantiated by the use of a specific caspase-1 inhibitor, Ac-YVAD-CMK. Wild-type mice treated with Ac-YVAD-CMK (10 mg/kg s.c. twice daily, initiated at time of CLP) did not have impaired clearance of a Pseudomonas challenge compared with that of sham mice and had significantly improved bacterial clearance compared with that of untreated CLP mice. Increased caspase-1 expression and activity after CLP injury appears to contribute to diminished innate immune function.
Circulating Activated and Effector Memory T Cells Are Associated with Calcification and Clonal Expansions in Bicuspid and Tricuspid Valves of Calcific Aortic Stenosis
Authors: Winchester Robert , Wiesendanger Margrit , O’Brien Will , Zhang Hui-Zhu , Maurer Mathew S. , Gillam Linda D. , Schwartz Allan , Marboe Charles , Stewart Allan S.
Published: June 2011

We sought to delineate further the immunological significance of T lymphocytes infiltrating the valve leaflets in calcific aortic stenosis (CAS) and determine whether there were associated alterations in circulating T cells. Using clonotypic TCR β-chain length and sequence analysis we confirmed that the repertoire of tricuspid CAS valves contains numerous expanded T cell clones with varying degrees of additional polyclonality, which was greatest in cases with severe calcification. We now report a similar proportion of clonal expansions in the much younger bicuspid valve CAS cases. Peripheral blood flow cytometry revealed elevations in HLA-DR+ activated CD8 cells and in the CD8+CD28nullCD57+ memory-effector subset that were significantly greater in both bicuspid and tricuspid CAS cases with more severe valve calcification. Lesser increases of CD4+CD28null T cells were identified, principally in cases with concurrent atherosclerotic disease. Upon immunostaining the CD8 T cells in all valves were mainly CD28null, and CD8 T cell percentages were greatest in valves with oligoclonal repertoires. T cell clones identified by their clonotypic sequence as expanded in the valve were also found expanded in the circulating blood CD28nullCD8+ T cells and to a lesser degree in the CD8+CD28+ subset, directly supporting the relationship between immunologic events in the blood and the valve. The results suggest that an ongoing systemic adaptive immune response is occurring in cases with bicuspid and tricuspid CAS, involving circulating CD8 T cell activation, clonal expansion, and differentiation to a memory-effector phenotype, with trafficking of T cells in expanded clones between blood and the valve.
Bruton’s Tyrosine Kinase Is Required for TLR-Dependent Heme Oxygenase-1 Gene Activation via Nrf2 in Macrophages
Authors: Vijayan Vijith , Baumgart-Vogt Eveline , Naidu Srivatsava , Qian Guofeng , Immenschuh Stephan
Published: June 2011

Heme oxygenase (HO)-1 is the inducible isoform of the rate-limiting enzyme of heme degradation and provides cytoprotection against oxidative stress by its products carbon monoxide and biliverdin. More recently, HO-1 has also been shown to exert immunomodulatory functions via cell type-specific anti-inflammatory effects in myeloid/macrophage cells. In the current study, it is demonstrated that Bruton's tyrosine kinase (Btk), the gene of which is mutated in the human immunodeficiency X-linked agammaglobulinemia, is involved in the upregulation of HO-1 gene expression via TLR signaling in macrophages. The specific Btk inhibitor LFM-A13 blocked HO-1 induction by the classical TLR4 ligand LPS in cell cultures of RAW264.7 monocytic cells and primary mouse alveolar macrophages. Moreover, upregulation of HO-1 gene expression was abrogated in LPS-stimulated alveolar macrophages from Btk−/− mice. Transfection studies with luciferase reporter gene constructs demonstrated that LPS-dependent induction of HO-1 promoter activity was attenuated by pharmacological Btk inhibition and by an overexpressed dominant-negative mutant of Btk. This induction was mediated by the transcription factor Nrf2, which is a master regulator of the antioxidant cellular defense. Accordingly, nuclear translocation of Nrf2 in LPS-treated macrophages was reduced by Btk inhibition. The generation of reactive oxygen species, but not that of NO, was involved in this regulatory pathway. Btk-dependent induction of HO-1 gene expression was also observed upon macrophage stimulation with ligands of TLR2, TLR6, TLR7, and TLR9, suggesting that Btk is required for HO-1 gene activation by major TLR pathways.
Cancer Exosomes Express CD39 and CD73, Which Suppress T Cells through Adenosine Production
Authors: Clayton Aled , Al-Taei Saly , Webber Jason , Mason Malcolm D. , Tabi Zsuzsanna
Published: June 2011

Extracellular adenosine is elevated in cancer tissue, and it negatively regulates local immune responses. Adenosine production from extracellular ATP has attracted attention as a mechanism of regulatory T cell-mediated immune regulation. In this study, we examined whether small vesicles secreted by cancer cells, called exosomes, contribute to extracellular adenosine production and hence modulate immune effector cells indirectly. We found exosomes from diverse cancer cell types exhibit potent ATP- and 5′AMP-phosphohydrolytic activity, partly attributed to exosomally expressed CD39 and CD73, respectively. Comparable levels of activity were seen with exosomes from pleural effusions of mesothelioma patients. In such fluids, exosomes accounted for 20% of the total ATP-hydrolytic activity. Exosomes can perform both hydrolytic steps sequentially to form adenosine from ATP. This exosome-generated adenosine can trigger a cAMP response in adenosine A2A receptor-positive but not A2A receptor-negative cells. Similarly, significantly elevated cAMP was also triggered in Jurkat cells by adding exosomes with ATP but not by adding exosomes or ATP alone. A proportion of healthy donor T cells constitutively express CD39 and/or CD73. Activation of T cells by CD3/CD28 cross-linking could be inhibited by exogenously added 5′AMP in a CD73-dependent manner. However, 5′AMP converted to adenosine by exosomes inhibits T cell activation independently of T cell CD73 expression. This T cell inhibition was mediated through the adenosine A2A receptor. In summary, the data highlight exosome enzymic activity in the production of extracellular adenosine, and this may play a contributory role in negative modulation of T cells in the tumor environment.
Anti-CD8 Antibodies Can Trigger CD8+ T Cell Effector Function in the Absence of TCR Engagement and Improve Peptide–MHCI Tetramer Staining
Authors: Clement Mathew , Ladell Kristin , Ekeruche-Makinde Julia , Miles John J. , Edwards Emily S. J. , Dolton Garry , Williams Tamsin , Schauenburg Andrea J. A. , Cole David K. , Lauder Sarah N. , Gallimore Awen M. , Godkin Andrew J. , Burrows Scott R. , Price David A. , Sewell Andrew K. , Wooldridge Linda
Published: June 2011

CD8+ T cells recognize immunogenic peptides presented at the cell surface bound to MHCI molecules. Ag recognition involves the binding of both TCR and CD8 coreceptor to the same peptide–MHCI (pMHCI) ligand. Specificity is determined by the TCR, whereas CD8 mediates effects on Ag sensitivity. Anti-CD8 Abs have been used extensively to examine the role of CD8 in CD8+ T cell activation. However, as previous studies have yielded conflicting results, it is unclear from the literature whether anti-CD8 Abs per se are capable of inducing effector function. In this article, we report on the ability of seven monoclonal anti-human CD8 Abs to activate six human CD8+ T cell clones with a total of five different specificities. Six of seven anti-human CD8 Abs tested did not activate CD8+ T cells. In contrast, one anti-human CD8 Ab, OKT8, induced effector function in all CD8+ T cells examined. Moreover, OKT8 was found to enhance TCR/pMHCI on-rates and, as a consequence, could be used to improve pMHCI tetramer staining and the visualization of Ag-specific CD8+ T cells. The anti-mouse CD8 Abs, CT-CD8a and CT-CD8b, also activated CD8+ T cells despite opposing effects on pMHCI tetramer staining. The observed heterogeneity in the ability of anti-CD8 Abs to trigger T cell effector function provides an explanation for the apparent incongruity observed in previous studies and should be taken into consideration when interpreting results generated with these reagents. Furthermore, the ability of Ab-mediated CD8 engagement to deliver an activation signal underscores the importance of CD8 in CD8+ T cell signaling.
Cyclosporine-Resistant, Rab27a-Independent Mobilization of Intracellular Preformed CD40 Ligand Mediates Antigen-Specific T Cell Help In Vitro
Authors: Koguchi Yoshinobu , Gardell Jennifer L. , Thauland Timothy J. , Parker David C.
Published: June 2011

CD40L is critically important for the initiation and maintenance of adaptive immune responses. It is generally thought that CD40L expression in CD4+ T cells is regulated transcriptionally and made from new mRNA following Ag recognition. However, recent studies with two-photon microscopy revealed that most cognate interactions between effector CD4+ T cells and APCs are too short for de novo synthesis of CD40L. Given that effector and memory CD4+ T cells store preformed CD40L (pCD40L) in lysosomal compartments and that pCD40L comes to the cell surface within minutes of antigenic stimulation, we and others have proposed that pCD40L might mediate T cell-dependent activation of cognate APCs during brief encounters in vivo. However, it has not been shown that this relatively small amount of pCD40L is sufficient to activate APCs, owing to the difficulty of separating the effects of pCD40L from those of de novo CD40L and other cytokines in vitro. In this study, we show that pCD40L surface mobilization is resistant to cyclosporine or FK506 treatment, while de novo CD40L and cytokine expression are completely inhibited. These drugs thus provide a tool to dissect the role of pCD40L in APC activation. We find that pCD40L mediates selective activation of cognate but not bystander APCs in vitro and that mobilization of pCD40L does not depend on Rab27a, which is required for mobilization of lytic granules. Therefore, effector CD4+ T cells deliver pCD40L specifically to APCs on the same time scale as the lethal hit of CTLs but with distinct molecular machinery.
Anticardiac Myosin Immunity and Chronic Allograft Vasculopathy in Heart Transplant Recipients
Authors: Kalache Safa , Dinavahi Rajani , Pinney Sean , Mehrotra Anita , Cunningham Madeleine W. , Heeger Peter S.
Published: June 2011

Chronic allograft vasculopathy (CAV) contributes to heart transplant failure, yet its pathogenesis is incompletely understood. Although cellular and humoral alloimmunity are accepted pathogenic mediators, animal models suggest that T cells and Abs reactive to graft-expressed autoantigens, including cardiac myosin (CM), could participate. To test the relationship between CAV and anti-CM autoimmunity in humans, we performed a cross-sectional study of 72 heart transplant recipients: 40 with CAV and 32 without. Sera from 65% of patients with CAV contained anti-CM Abs, whereas <10% contained Abs to other autoantigens (p < 0.05), and only 18% contained anti-HLA Abs (p < 0.05 versus anti-CM). In contrast, 13% of sera from patients without CAV contained anti-CM Abs (p < 0.05; odds ratio [OR], associating CAV with anti-CM Ab = 13, 95% confidence interval [CI] 3.79–44.6). Multivariable analysis confirmed the association to be independent of time posttransplant and the presence of anti-HLA Abs (OR = 28, 95% CI 5.77–133.56). PBMCs from patients with CAV responded more frequently to, and to a broader array of, CM-derived peptides than those without CAV (p = 0.01). Detection of either CM–peptide-reactive T cells or anti-CM Abs was highly and independently indicative of CAV (OR = 45, 95% CI 4.04–500.69). Our data suggest detection of anti-CM immunity could be used as a biomarker for outcome in heart transplantation recipients and support the need for further studies to assess whether anti-CM immunity is a pathogenic mediator of CAV.
Developmental Arrest of T Cells in Rpl22-Deficient Mice Is Dependent upon Multiple p53 Effectors
Authors: Stadanlick Jason E. , Zhang Zhiqiang , Lee Sang-Yun , Hemann Mike , Biery Matthew , Carleton Michael O. , Zambetti Gerard P. , Anderson Stephen J. , Oravecz Tamas , Wiest David L.
Published: June 2011

αβ and γδ lineage T cells are thought to arise from a common CD4–CD8– progenitor in the thymus. However, the molecular pathways controlling fate selection and maturation of these two lineages remain poorly understood. We demonstrated recently that a ubiquitously expressed ribosomal protein, Rpl22, is selectively required for the development of αβ lineage T cells. Germline ablation of Rpl22 impairs development of αβ lineage, but not γδ lineage, T cells through activation of a p53-dependent checkpoint. In this study, we investigate the downstream effectors used by p53 to impair T cell development. We found that many p53 targets were induced in Rpl22−/− thymocytes, including miR-34a, PUMA, p21waf, Bax, and Noxa. Notably, the proapoptotic factor Bim, while not a direct p53 target, was also strongly induced in Rpl22−/− T cells. Gain-of-function analysis indicated that overexpression of miR-34a caused a developmental arrest reminiscent of that induced by p53 in Rpl22-deficient T cells; however, only a few p53 targets alleviated developmental arrest when individually ablated by gene targeting or knockdown. Co-elimination of PUMA and Bim resulted in a nearly complete restoration of development of Rpl22−/− thymocytes, indicating that p53-mediated arrest is enforced principally through effects on cell survival. Surprisingly, co-elimination of the primary p53 regulators of cell cycle arrest (p21waf) and apoptosis (PUMA) actually abrogated the partial rescue caused by loss of PUMA alone, suggesting that the G1 checkpoint protein p21waf facilitates thymocyte development in some contexts.
Absence of Vasoactive Intestinal Peptide Expression in Hematopoietic Cells Enhances Th1 Polarization and Antiviral Immunity in Mice
Authors: Li Jian-Ming , Southerland Lauren , Hossain Mohammad S. , Giver Cynthia R. , Wang Ying , Darlak Kasia , Harris Wayne , Waschek James , Waller Edmund K.
Published: June 2011

Vasoactive intestinal peptide (VIP) induces regulatory dendritic cells (DC) in vitro that inhibit cellular immune responses. We tested the role of physiological levels of VIP on immune responses to murine CMV (mCMV) using VIP-knockout (VIP-KO) mice and radiation chimeras engrafted with syngenic VIP-KO hematopoietic cells. VIP-KO mice had less weight loss and better survival following mCMV infection compared with wild-type (WT) littermates. mCMV-infected VIP-KO mice had lower viral loads, faster clearance of virus, with increased numbers of IFN-γ+ NK and NKT cells, and enhanced cytolytic activity of NK cells. Adaptive antiviral cellular immunity was increased in mCMV-infected VIP-KO mice compared with WT mice, with more Th1/Tc1-polarized T cells, fewer IL-10+ T cells, and more mCMV-M45 epitope peptide MHC class I tetramer+ CD8+ T cells (tetramer+ CD8 T cells). mCMV-immune VIP-KO mice had enhanced ability to clear mCMV peptide-pulsed target cells in vivo. Enhanced antiviral immunity was also seen in WT transplant recipients engrafted with VIP-KO hematopoietic cells, indicating that VIP synthesized by neuronal cells did not suppress immune responses. Following mCMV infection there was a marked upregulation of MHC-II and CD80 costimulatory molecule expression on DC from VIP-KO mice compared with DC from WT mice, whereas programmed death-1 and programmed death ligand-1 expression were upregulated in activated CD8+ T cells and DC, respectively, in WT mice, but not in VIP-KO mice. Because the absence of VIP in immune cells increased innate and adaptive antiviral immunity by altering costimulatory and coinhibitory pathways, selective targeting of VIP signaling represents an attractive therapeutic target to enhance antiviral immunity.