bluuebunny/crossref_metadata_2025 huggingface dataset:
Human brain endothelial cells endeavor to immunoregulate CD8 T cells via PD-1 ligand expression in multiple sclerosis
Authors: Pittet Camille L , Newcombe Jia , Prat Alexandre , Arbour Nathalie
Published: November 2011

Background

Multiple sclerosis (MS), an inflammatory disease of the central nervous system (CNS), is characterized by blood-brain barrier (BBB) disruption and massive infiltration of activated immune cells. Engagement of programmed cell death-1 (PD-1) expressed on activated T cells with its ligands (PD-L1 and PD-L2) suppresses T cell responses. We recently demonstrated in MS lesions elevated PD-L1 expression by glial cells and absence of PD-1 on many infiltrating CD8 T cells. We have now investigated whether human brain endothelial cells (HBECs), which maintain the BBB, can express PD-L1 or PD-L2 and thereby modulate T cells.

Methods

We used primary cultures of HBECs isolated from non-tumoral CNS tissue either under basal or inflamed conditions. We assessed the expression of PD-L1 and PD-L2 using qPCR and flow cytometry. Human CD8 T cells were isolated from peripheral blood of healthy donors and co-cultured with HBECs. Following co-culture with HBECs, proliferation and cytokine production by human CD8 T cells were measured by flow cytometry whereas transmigration was determined using a well established in vitro model of the BBB. The functional impact of PD-L1 and PD-L2 provided by HBECs was determined using blocking antibodies. We performed immunohistochemistry for the detection of PD-L1 or PD-L2 concurrently with caveolin-1 (a cell specific marker for endothelial cells) on post-mortem human brain tissues obtained from MS patients and normal controls.

Results

Under basal culture conditions, PD-L2 is expressed on HBECs, whilst PD-L1 is not detected. Both ligands are up-regulated under inflammatory conditions. Blocking PD-L1 and PD-L2 leads to increased transmigration and enhanced responses by human CD8 T cells in co-culture assays. Similarly, PD-L1 and PD-L2 blockade significantly increases CD4 T cell transmigration. Brain endothelium in normal tissues and MS lesions does not express detectable PD-L1; in contrast, all blood vessels in normal brain tissues are PD-L2-positive, while only about 50% express PD-L2 in MS lesions.

Conclusions

Our observations suggest that brain endothelial cells contribute to control T cell transmigration into the CNS and immune responses via PD-L2 expression. However, such impact is impaired in MS lesions due to downregulation of endothelium PD-L2 levels.
Plasma proteome analysis in HTLV-1-associated myelopathy/tropical spastic paraparesis
Authors: Kirk Paul DW , Witkover Aviva , Courtney Alan , Lewin Alexandra M , Wait Robin , Stumpf Michael PH , Richardson Sylvia , Taylor Graham P , Bangham Charles RM
Published: November 2011

Background

Human T lymphotropic virus Type 1 (HTLV-1) causes a chronic inflammatory disease of the central nervous system known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM) which resembles chronic spinal forms of multiple sclerosis (MS). The pathogenesis of HAM remains uncertain. To aid in the differential diagnosis of HAM and to identify pathogenetic mechanisms, we analysed the plasma proteome in asymptomatic HTLV-1 carriers (ACs), patients with HAM, uninfected controls, and patients with MS. We used surface-enhanced laser desorption-ionization (SELDI) mass spectrometry to analyse the plasma proteome in 68 HTLV-1-infected individuals (in two non-overlapping sets, each comprising 17 patients with HAM and 17 ACs), 16 uninfected controls, and 11 patients with secondary progressive MS. Candidate biomarkers were identified by tandem Q-TOF mass spectrometry.

Results

The concentrations of three plasma proteins - high [β2-microglobulin], high [Calgranulin B], and low [apolipoprotein A2] - were specifically associated with HAM, independently of proviral load. The plasma [β2-microglobulin] was positively correlated with disease severity.

Conclusions

The results indicate that monocytes are activated by contact with activated endothelium in HAM. Using β2-microglobulin and Calgranulin B alone we derive a diagnostic algorithm that correctly classified the disease status (presence or absence of HAM) in 81% of HTLV-1-infected subjects in the cohort.
Incidence and risk factors of antiretroviral treatment failure in treatment-naïve HIV-infected patients at Chiang Mai University Hospital, Thailand
Authors: Khienprasit Nitta , Chaiwarith Romanee , Sirisanthana Thira , Supparatpinyo Khuanchai
Published: November 2011

Background

The use of combination antiretroviral therapy (cART) has become a standard of care for the treatment of HIV infection. However, cost and resistance to cART are major obstacles for access to treatment especially in resource-limited settings. In this study, we aimed to determine the incidence and risk factors of treatment failure in a cohort of treatment-naïve Thai HIV-infected patients.

Methods

A retrospective cohort study was conducted among HIV-infected patients initiating their first cART at Chiang Mai University Hospital, Thailand.

Results

From January 2002 to December 2008, 788 patients were enrolled; 365 were male (46.3%), and the mean age was 37.9 ± 8.6 years. The median baseline CD4 count was 57.7 cells/mm3 (IQR 22, 127). GPO-VIR® (a fixed-dose combination of lamivudine, stavudine, and nevirapine) was the most common prescribed cART (657 patients, 83.4%). Seventy-six patients developed virological failure given the cumulative incidence of 9.6%. The incidence of virological failure was 2.79 (95% CI 2.47, 3.14) cases per 100 person years. Poor adherence was the strongest predictor for virological failure. Of 535 immunologically evaluable patients, 179 (33.5%) patients developed immunological failure. A low CD4 cell count at baseline (< 100 cells/mm3) and the increment of CD4 cell count of < 50 cell/mm3 after 6 months of cART were the predictors for immunological failure (p < 0.001).

Conclusions

This study demonstrated that even in resource-limited settings, the high rate of success could be expected in the cohort with good and sustainable drug adherence. Poor adherence, older age, and low baseline CD4 cell count are the predictors for unfavorable outcome of cART.
Constructing stochastic models from deterministic process equations by propensity adjustment
Authors: Wu Jialiang , Vidakovic Brani , Voit Eberhard O
Published: November 2011

Background

Gillespie's stochastic simulation algorithm (SSA) for chemical reactions admits three kinds of elementary processes, namely, mass action reactions of 0th, 1st or 2nd order. All other types of reaction processes, for instance those containing non-integer kinetic orders or following other types of kinetic laws, are assumed to be convertible to one of the three elementary kinds, so that SSA can validly be applied. However, the conversion to elementary reactions is often difficult, if not impossible. Within deterministic contexts, a strategy of model reduction is often used. Such a reduction simplifies the actual system of reactions by merging or approximating intermediate steps and omitting reactants such as transient complexes. It would be valuable to adopt a similar reduction strategy to stochastic modelling. Indeed, efforts have been devoted to manipulating the chemical master equation (CME) in order to achieve a proper propensity function for a reduced stochastic system. However, manipulations of CME are almost always complicated, and successes have been limited to relative simple cases.

Results

We propose a rather general strategy for converting a deterministic process model into a corresponding stochastic model and characterize the mathematical connections between the two. The deterministic framework is assumed to be a generalized mass action system and the stochastic analogue is in the format of the chemical master equation. The analysis identifies situations: where a direct conversion is valid; where internal noise affecting the system needs to be taken into account; and where the propensity function must be mathematically adjusted. The conversion from deterministic to stochastic models is illustrated with several representative examples, including reversible reactions with feedback controls, Michaelis-Menten enzyme kinetics, a genetic regulatory motif, and stochastic focusing.

Conclusions

The construction of a stochastic model for a biochemical network requires the utilization of information associated with an equation-based model. The conversion strategy proposed here guides a model design process that ensures a valid transition between deterministic and stochastic models.
Pyosalpinx as a sequela of labial fusion in a post-menopausal woman: a case report
Authors: Tsianos George I , Papatheodorou Stefania I , Michos George M , Koliopoulos George , Stefos Theodor
Published: November 2011

Introduction

Complete labia fusion is a rare clinical entity in post-menopausal women. The most common complications of this presentation are infections of the urinary tract and retention of urine in the vagina. We present the case of a post-menopausal woman with adnexal mass and abdominal pain due to fusion of the labia majora. To the best of our knowledge this is the first report in the literature of this complication.

Case presentation

A 78-year-old Caucasian woman was admitted to our hospital due to abdominal pain and urination difficulty, along with fever and leucocytosis. On examination the labial majora were fused. Computed tomography of the abdomen revealed a cystic formation in the anatomical area of the right adnexa. Our patient had developed a pyosalpinx as a Sequela of labial fusion. At laparoscopy the right pyosalpinx was identified and resected, whereas the labia majora were reconstructed via dissection and separation.

Conclusions

Labial fusion is a rare clinical entity in post-menopausal women and can have serious and unexpected complications. Though this presentation is rare, a clinical examination must be performed in detail in order to gain valuable information for an accurate diagnosis. Post-operational instruction must be given to patients in order to prevent the re-occurrence of the fusion and its complications.
Proliferating cell nuclear antigen is required for loading of the SMCX/KMD5C histone demethylase onto chromatin
Authors: Liang Zhihui , Diamond Marc , Smith Johanna A , Schnell Matthias , Daniel René
Published: November 2011

Background

Histone methylation is regulated by a large number of histone methyltransferases and demethylases. The recently discovered SMCX/KMD5C demethylase has been shown to remove methyl residues from lysine 4 of histone H3 (H3K4), and constitutes an important component of the regulatory element-1-silencing transcription factor (REST) protein complex. However, little is known about the cellular mechanisms that control SMCX activity and intracellular trafficking.

Results

In this study, we found that small interfering RNA-mediated knockdown of proliferating cell nuclear antigen (PCNA) resulted in the reduction of the chromatin-bound SMCX fraction. We identified a PCNA-interaction protein motif (PIP box) in the SMCX protein. Using site-directed mutagenesis, we found that the amino acids of the SMCX PIP box are involved in the association of SMCX with PCNA and its interaction with chromatin.

Conclusions

Our data indicate that the intracellular trafficking of SMCX is controlled by its association with PCNA.
Peptide immunotherapy for childhood allergy ‐ addressing translational challenges
Authors: Mackenzie Karen J , Anderton Stephen M , Schwarze Jürgen
Published: November 2011

Allergic sensitisation usually begins early in life. The number of allergens a patient is sensitised to can increase over time and the development of additional allergic conditions is increasingly recognised. Targeting allergic disease in childhood is thus likely to be the most efficacious means of reducing the overall burden of allergic disease. Specific immunotherapy involves administering protein allergen to tolerise allergen reactive CD4+ T cells, thought key in driving allergic responses. Yet specific immunotherapy risks allergic reactions including anaphylaxis as a consequence of preformed allergen‐specific IgE antibodies binding to the protein, subsequent cross‐linking and mast cell degranulation. CD4+ T cells direct their responses to short “immunodominant” peptides within the allergen. Such peptides can be given therapeutically to induce T cell tolerance without facilitating IgE cross‐linking. Peptide immunotherapy (PIT) offers attractive treatment potential for allergic disease. However, PIT has not yet been shown to be effective in children. This review discusses the immunological mechanisms implicated in PIT and briefly covers outcomes from adult PIT trials. This provides a context for discussion of the challenges for the application of PIT, both generally and more specifically in relation to children.
Production optimization of cyanophycinase ChpEal from Pseudomonas alcaligenes DIP1
Authors: Sallam Ahmed , Kalkandzhiev Dimitar , Steinbüchel Alexander
Published: November 2011

Pseudomonas alcaligenes DIP1 produces an extracellular cyanophycinase (CphEal). The corresponding gene (cphE

al
) was identified from subclones of a genomic DNA gene library by heterologously expressing the functionally active enzyme in Escherichia coli. The nucleotide sequence of the gene (1260 base pairs) was determined indicating a theoretical mass of 43.6 kDa (mature CphEal) plus a leader peptide of 2,6 kDa which corresponds well to the apparent molecular mass of 45 kDa as revealed by SDS-PAGE. The enzyme exhibited a high sequence identity of 91% with the extracellular cyanophycinase from P. anguilliseptica strain BI and carried an N-terminal Sec secretion signal peptide. Analysis of the amino acid sequence of cph E revealed a putative catalytic triad consisting of the serine motif GXSXG plus a histidine and a glutamate residue, suggesting a catalytic mechanism similar to serine-type proteases. The cyanophycinase (CphEal) was heterologously produced in two different E. coli strains (Top10 and BL21(DE3)) from two plasmid vectors (pBBR1MCS-4 and pET-23a(+)). The signal peptide of CphEal was cleaved in E. coli, suggesting active export of the protein at least to the periplasm. Substantial enzyme activity was also present in the culture supernatants. The extracellular cyanophycinase activities in E. coli were higher than activities in the wild type P. alcaligenes DIP1 in complex LB medium. Highest extracellular enzyme production was achieved with E. coli BL21(DE3) expressing CphEal from pBBR1MCS-4. Using M9 minimal medium was less effective, but the relatively low cost of mineral salt media makes these results important for the industrial-scale production of dipeptides from cyanophycin.
Nomogram for Predicting the Benefit of Adjuvant Chemoradiotherapy for Resected Gallbladder Cancer
Authors: Wang Samuel J. , Lemieux Andrew , Kalpathy-Cramer Jayashree , Ord Celine B. , Walker Gary V. , Fuller C. David , Kim Jong-Sung , Thomas Charles R.
Published: November 2011

Purpose

Although adjuvant chemoradiotherapy for resected gallbladder cancer may improve survival for some patients, identifying which patients will benefit remains challenging because of the rarity of this disease. The specific aim of this study was to create a decision aid to help make individualized estimates of the potential survival benefit of adjuvant chemoradiotherapy for patients with resected gallbladder cancer.

Methods

Patients with resected gallbladder cancer were selected from the Surveillance, Epidemiology, and End Results (SEER) –Medicare database who were diagnosed between 1995 and 2005. Covariates included age, race, sex, stage, and receipt of adjuvant chemotherapy or chemoradiotherapy (CRT). Propensity score weighting was used to balance covariates between treated and untreated groups. Several types of multivariate survival regression models were constructed and compared, including Cox proportional hazards, Weibull, exponential, log-logistic, and lognormal models. Model performance was compared using the Akaike information criterion. The primary end point was overall survival with or without adjuvant chemotherapy or CRT.

Results

A total of 1,137 patients met the inclusion criteria for the study. The lognormal survival model showed the best performance. A Web browser–based nomogram was built from this model to make individualized estimates of survival. The model predicts that certain subsets of patients with at least T2 or N1 disease will gain a survival benefit from adjuvant CRT, and the magnitude of benefit for an individual patient can vary.

Conclusion

A nomogram built from a parametric survival model from the SEER-Medicare database can be used as a decision aid to predict which gallbladder patients may benefit from adjuvant CRT.
Manuscrito Del Aperreamiento (Manuscript of the Dogging): A “Dogging” And Its Implications for Early Colonial Cholula
Authors: Diel Lori Boornazian
Published: November 2011

The Manuscrito del aperreamiento (Manuscript of the Dogging), from Cholula ca. 1560, presents a graphic image of a dog attacking a bound indigenous priest. Certainly appalling to modern viewers, the work is often seen as an indictment against the Spaniards pictured. In this article, I consider this traditional interpretation and show that it is not entirely satisfactory. Though the Spaniards pictured in the Manuscrito were each accused of cruelties against indigenous peoples, none of these accusations mention the spectacular dogging pictured in the Manuscrito. I then provide a more nuanced reading of the imagery in the Manuscrito and a consideration of its early colonial context and argue that while the work does document a clash of Spaniards versus indigenes, it also establishes a contrast between a Christian indigenous leader and his pagan countrymen. In so doing, the Manuscrito communicates the culpability of the indigenous victims for their harsh punishment. By comparing this image with doggings in other pictorial sources, I show that violent images such as these communicated both the rebellious nature of the indigenous victims and the cruelties of the Spanish conquerors.
Politics, Culture, and the Security of France: A Reinterpretation of French Foreign and Security Policy after the First World War
Authors: Jackson Peter
Published: November 2011

French foreign and security policy after the First World War has long been depicted as an attempt to use traditional strategies based on the balance of power and alliance politics to compel Germany to comply with its obligations under the Treaty of Versailles. The change to a more conciliatory policy in 1924 is typically understood as a response to pressure from Britain and the United States, as well as to French weakness. This interpretation ignores important internationalist currents in French thinking about security during the late nineteenth and early twentieth centuries and their impact during and after the First World War. It also fails to account for key developments in the French public sphere after that conflict. This article argues that an approach to security best described as “juridical internationalism” played an increasingly influential role in shaping national security policy during the early 1920s. The result was a gradual move away from a policy of confrontation and a growing emphasis on compulsory arbitration and binding mutual assistance. This process culminated in the Locarno Accords of 1925.

La politique étrangère en matière de sécurité française après la Première Guerre mondiale a longtemps été dépeinte comme une tentative d’exécuter les stratégies classiques fondées sur l’équilibre des puissances et une politique d’alliances pour contraindre l’Allemagne à se conformer aux obligations du traité de Versailles. En outre, le changement vers une politique plus conciliante en 1924 est systématiquement compris d’une part comme une réponse à la pression commune de la Grande-Bretagne et des Etats-Unis et d’autre part comme un effet de l’affaiblissement de la France. Cette interprétation dominante ignore les importants courants internationalistes dans la pensée française en matière de sécurité depuis la fin du dix-neuvième siècle et au début du vingtième siècle et leur impact sur l’élite après la Première Guerre mondiale. D’autre part, ceci ne tient pas compte des développements importants au sein de la sphère publique au lendemain du conflit. Cet article défend l’idée qu’une autre approche de la sécurité, appelée « internationalisme juridique », a émergé et joué un rôle croissant dans l’édification d’une politique de sécurité nationale au début des années 1920. Le résultat fut un éloignement progressif d’une politique de confrontation fondée sur des méthodes traditionnelles et une insistance croissante sur l’arbitrage obligatoire et l’assistance mutuelle. Ce processus connut son apogée avec les accords de Locarno en 1925.
Fighting “Communist Banditry” in French Vietnam: The Rhetoric of Repression after the Yen Bay Uprising, 1930–1932
Authors: Thomas Martin
Published: November 2011

One of the most striking aspects of the Vietnamese political disorders that erupted in Tonkin and Annam in 1930–31 was how the French colonial authorities represented them. The colonial authorities developed a distinct rhetoric of repression in the blame games that followed the outbreak of the Yen Bay mutiny in February 1930 and in the more protracted unrest associated with the Nghe-Tinh Soviets in Annam. The depiction of concerted political violence as self-interested criminal activity delegitimized its organizers, their motives, and their claims. Pointing to traditions of rural banditry and local particularism, Governor-General Pierre Pasquier’s administration insisted to sometimes skeptical officials and parliamentarians in France that the extreme repression meted out by the colonial security forces was effective, appropriate, and popularly understood. In this way Yen Bay’s rhetoric of repression drew on an established language of colonial social control to justify a strategy of extreme state violence.

Un des aspects déroutants des désordres politiques en Indochine française de 1930–31 fut la multiplicité de complots dits « banditismes » ou « criminels » par les autorités coloniales et militaires. Les efforts d’expiation et de blâme montés par l’administration du gouverneur-général Pierre Pasquier et ses collègues furent dans la nature des choses pour les organisations coloniales, elles-mêmes embarrassées par un éclat de violence sociale inattendue, accompagné d’une « rhétorique de répression » distincte. Ces objectifs étaient la criminalisation des rebelles et, par conséquent, l’imputation des motifs infantiles aux mouvements communistes et nationalistes vietnamiens. Le Parti communiste indochinois n’y échappa pas; toutefois, les fonctionnaires du Ministère des Colonies et une minorité de parlementaires français restèrent franchement sceptiques face aux explications officielles de la répression sanglante au Tonkin et à Annam. Pourtant, bien que cette rhétorique ne tienne aucun compte des preuves des soulèvements populaires et d’un mouvement national en voie de développement, elle sert bien de tactique coloniale. L’accusation d’un banditisme, provenu des traditions et pratiques des pirates tonkinois, refuse la signification politique des événements en même temps qu’elle justifie les méthodes violentes des forces de sécurité coloniale.
Plots and Rumors: Conspiracy Theories and the Six Février 1934
Authors: Jenkins Brian
Published: November 2011

The events surrounding the six février 1934 riots were accompanied by intense rumor and speculation, with political rivals accusing each other of conspiracy and subversion at every turn. Following suit, historians have also been preoccupied with the mechanics of these conspiracy theories, seeing them as the acid test of whether the regime was in any kind of danger. On this basis most scholars have concluded that there was no “plot,” no attempted coup, and therefore no significant threat. This article argues that this whole perspective is misguided. It misjudges how such crises develop, how popular mobilizations gather momentum, and how they escape the control of those who might wish to manipulate them. The real importance of the conspiracy theories lies not in their evidential foundations but in the fact that they were widely believed and therefore influenced behavior on both sides. They were therefore a vital ingredient in the creation of political emergency.

Les événements du six février 1934 se déroulent dans un climat fébrile de rumeur et de conjecture, les rivaux politiques s’entraccusant à tout moment de subversion et de conspiration. Les historiens, à leur tour, restent préoccupés des mécanismes de ces thèses du complot, censées prouver définitivement si ou non le régime était en danger. Ainsi, la plupart d’entre eux arrivent à la conclusion qu’il n’y avait ni complot ni coup d’état manqué, et par conséquent aucune menace importante. On propose ici que cette perspective est fallacieuse. Elle méconnaît les modalités des crises de ce genre, l’élan vital de ces mobilisations populaires qui échappent au contrôle de ceux qui auraient voulu les manipuler. L’importance de ces thèses du complot réside moins dans le domaine des faits que dans les perceptions: elles étaient très largement acceptées, elles ont façonné le comportement des acteurs et elles ont ainsi contribué à préparer le climat d’urgence politique.
Democratic Modernism: Rethinking the Politics of Early Twentieth-Century Fiction in China and Europe
Authors: Veg Sebastian
Published: November 2011

This article attempts to bring a new perspective to the debate on Chinese modernism and, in so doing, to reflect on the idea of modernism itself. Rather than opposing European “high modernists” and an early twentieth-century Chinese literature defined by Enlightenment and nineteenth-century style literary realism, it proposes to consider Lu Xun as a modernist writer and uses a comparative perspective to underscore his commonalities with European modernism. Comparing “The True story of Ah Q” with Brecht's The Good Person of Szechwan and Kafka's “Building the Great Wall of China,” the article argues that what brings these authors together is a unique understanding of democracy as the defining trait of modernity. This translates into a democratic pragmatics, in which moral norms and historical laws are fractured and questioned, leaving an “empty place” (Claude Lefort) at the center of the literary text, which echoes the empty center of modern democracy.
The Politics of Hindu “Tolerance”
Authors: Rajan Rajeswari Sunder
Published: November 2011

That the escalating Hindu violence against minorities has produced a crisis for secularism in present-day India—but not for Hinduism—is an intriguing fact that calls for further analysis. This essay attempts a reexamination of the split between Hinduism and Hindutva, purportedly representing “true” religion and “politicized” religion, and the mapping of this division onto the religious tenet of tolerance and its political exhaustion, respectively, and questions the explanatory value of this narrative. It examines the concept and genealogy of “tolerance” with a view to understanding how it became so central to defining Hinduism itself. Although tolerance is offered as a constitutive or perennial aspect of Hinduism's religious tradition, its prominence in Hinduism's self-description is actually of recent vintage. In the independent Indian nation-state, the dominance of Hinduism in a multireligious context could be checked only by making Indian “secularism” an aspect of, indeed dependent upon, Hindu tolerance. While Ashis Nandy has famously invoked tolerance as the preferred alternative to secularism in the Indian context, this essay argues that secularism in India has all along been (nothing but) (Hindu) tolerance. If tolerance is integral to the rhetoric of Hinduism, historically it has been equally integral to the rhetoric of secular nationalism. Both Hinduism and Hindutva are modern constructs, and although different in their interpretation of the attitude that the Hindu majority community will adopt toward other religious communities in India—the one tolerant and the other intolerant—are essentially alike in envisaging national coexistence as the framing politics of this concern.
Biography as Erasure: Louis Armstrong's Radical Light
Authors: Merod Jim
Published: November 2011

Louis Armstrong's career inaugurated the commercial viability of jazz for five decades. It also created both the structural conditions and critical reception that allowed jazz to emerge into a “classical” art form, still in the process of reshaping itself today. Armstrong's life, however, has often been inadequately comprehended and derogated despite evidence to the contrary. From the distance of four decades since his death, Armstrong can be seen as a uniquely self-directed man whose artistic authority and self-confidence were continuously under siege from multiple sources without diminishing his life, his art, or his legacy as an iconoclastic, genuinely transitional figure in the emergence of twentieth-century culture. His status as the first Global Citizen, representing his race and his country, is augmented by his anomalous “postracial” identity as a representative of human good will and the (imperfectly defined) human capacity for open and transcendent radiance of consciousness beyond metonymic identities. His example of joyful creativity offers a propaedeutic advantage for the incommensurable secularity of emerging humanistic work intersecting with increasingly technologically mediated scientific explorations of “knowing” as well as of consciousness and its cosmic metascape.
Mastermind-like 1 (MamL1) and mastermind-like 3 (MamL3) are essential for Notch signaling in vivo
Authors: Oyama Toshinao , Harigaya Kenichi , Sasaki Nobuo , Okamura Yoshiaki , Kokubo Hiroki , Saga Yumiko , Hozumi Katsuto , Suganami Akiko , Tamura Yutaka , Nagase Takahiro , Koga Hisashi , Nishimura Motoi , Sakamoto Reiko , Sato Mitsuharu , Yoshida Nobuaki , Kitagawa Motoo
Published: November 2011

Mastermind (Mam) is one of the elements of Notch signaling, a system that plays a pivotal role in metazoan development. Mam proteins form transcriptionally activating complexes with the intracellular domains of Notch, which are generated in response to the ligand-receptor interaction, and CSL DNA-binding proteins. In mammals, three structurally divergent Mam isoforms (MamL1, MamL2 and MamL3) have been identified. There have also been indications that Mam interacts functionally with various other transcription factors, including the p53 tumor suppressor, β-catenin and NF-κB. We have demonstrated previously that disruption of MamL1 causes partial deficiency of Notch signaling in vivo. However, MamL1-deficient mice did not recapitulate total loss of Notch signaling, suggesting that other members could compensate for the loss or that Notch signaling could proceed in the absence of Mam in certain contexts. Here, we report the generation of lines of mice null for MamL3. Although MamL3-null mice showed no apparent abnormalities, mice null for both MamL1 and MamL3 died during the early organogenic period with classic pan-Notch defects. Furthermore, expression of the lunatic fringe gene, which is strictly controlled by Notch signaling in the posterior presomitic mesoderm, was undetectable in this tissue of the double-null embryos. Neither of the single-null embryos exhibited any of these phenotypes. These various roles of the three Mam proteins could be due to their differential physical characteristics and/or their spatiotemporal distributions. These results indicate that engagement of Mam is essential for Notch signaling, and that the three Mam isoforms have distinct roles in vivo.
Chromosome silencing mechanisms in X-chromosome inactivation: unknown unknowns
Authors: Brockdorff Neil
Published: November 2011

Fifty years ago, Mary Lyon hypothesised that one of the two X chromosomes in female mammalian cells is inactivated at random during early embryogenesis and that the inactive X is then stably maintained through all subsequent cell divisions. Although Lyon’s hypothesis is now widely regarded as fact, we should not forget that her conceptual leap met with considerable resistance from the scientific establishment at the time – a common response to new ideas. Taking this point as a theme, I discuss our current understanding of the molecular mechanism of chromosome silencing in X-chromosome inactivation and focus on topics where new findings are challenging the prevailing view.
Roles of Hedgehog pathway components and retinoic acid signalling in specifying zebrafish ventral spinal cord neurons
Authors: England Samantha , Batista Manuel F. , Mich John K. , Chen James K. , Lewis Katharine E.
Published: November 2011

In mouse, Hedgehog (Hh) signalling is required for most ventral spinal neurons to form. Here, we analyse the spinal cord phenotype of zebrafish maternal-zygotic smoothened (MZsmo) mutants that completely lack Hh signalling. We find that most V3 domain cells and motoneurons are lost, whereas medial floorplate still develops normally and V2, V1 and V0v cells form in normal numbers. This phenotype resembles that of mice that lack both Hh signalling and Gli repressor activity. Ventral spinal cord progenitor domain transcription factors are not expressed at 24 hpf in zebrafish MZsmo mutants. However, pMN, p2 and p1 domain markers are expressed at early somitogenesis stages in these mutants. This suggests that Gli repressor activity does not extend into zebrafish ventral spinal cord at these stages, even in the absence of Hh signalling. Consistent with this, ectopic expression of Gli3R represses ventral progenitor domain expression at these early stages and knocking down Gli repressor activity rescues later expression. We investigated whether retinoic acid (RA) signalling specifies ventral spinal neurons in the absence of Hh signalling. The results suggest that RA is required for the correct number of many different spinal neurons to form. This is probably mediated, in part, by an effect on cell proliferation. However, V0v, V1 and V2 cells are still present, even in the absence of both Hh and RA signalling. We demonstrate that Gli1 has a Hh-independent role in specifying most of the remaining motoneurons and V3 domain cells in embryos that lack Hh signalling, but removal of Gli1 activity does not affect more dorsal neurons.
Fifty years of X-inactivation research
Authors: Gendrel Anne-Valerie , Heard Edith
Published: November 2011

The third X-inactivation meeting ‘Fifty years of X-inactivation research’, which celebrated the fiftieth anniversary of Mary Lyon’s formulation of the X-inactivation hypothesis, was an EMBO workshop held in Oxford, UK, in July 2011. This conference brought together the usual suspects from the field, as well as younger researchers, to discuss recent advances in X-inactivation research. Here, we review the results presented at the meeting and highlight some of the exciting progress that has been made. We also discuss the future challenges for the field, which aim to further our understanding of the developmental regulation of X inactivation, the randomness (or skewing) of X inactivation, and the diverse strategies used by mammalian species to mediate X inactivation.
ID4 regulates mammary gland development by suppressing p38MAPK activity
Authors: Dong Jie , Huang Shixia , Caikovski Marian , Ji Shaoquan , McGrath Amanda , Custorio Myra G. , Creighton Chad J. , Maliakkal Paul , Bogoslovskaia Ekaterina , Du Zhijun , Zhang Xiaomei , Lewis Michael T. , Sablitzky Fred , Brisken Cathrin , Li Yi
Published: November 2011

The ID family of helix-loop-helix proteins regulates cell proliferation and differentiation in many different developmental pathways, but the functions of ID4 in mammary development are unknown. We report that mouse Id4 is expressed in cap cells, basal cells and in a subset of luminal epithelial cells, and that its targeted deletion impairs ductal expansion and branching morphogenesis as well as cell proliferation induced by estrogen and/or progesterone. We discover that p38MAPK is activated in Id4-null mammary cells. p38MAPK is also activated following siRNA-mediated Id4 knockdown in transformed mammary cells. This p38MAPK activation is required for the reduced proliferation and increased apoptosis in Id4-ablated mammary glands. Therefore, ID4 promotes mammary gland development by suppressing p38MAPK activity.
Regulation ofDrosophilaglial cell proliferation by Merlin-Hippo signaling
Authors: Reddy B. V. V. G. , Irvine Kenneth D.
Published: November 2011

Glia perform diverse and essential roles in the nervous system, but the mechanisms that regulate glial cell numbers are not well understood. Here, we identify and characterize a requirement for the Hippo pathway and its transcriptional co-activator Yorkie in controlling Drosophila glial proliferation. We find that Yorkie is both necessary for normal glial cell numbers and, when activated, sufficient to drive glial over-proliferation. Yorkie activity in glial cells is controlled by a Merlin-Hippo signaling pathway, whereas the upstream Hippo pathway regulators Fat, Expanded, Crumbs and Lethal giant larvae have no detectable role. We extend functional characterization of Merlin-Hippo signaling by showing that Merlin and Hippo can be physically linked by the Salvador tumor suppressor. Yorkie promotes expression of the microRNA gene bantam in glia, and bantam promotes expression of Myc, which is required for Yorkie and bantam-induced glial proliferation. Our results provide new insights into the control of glial growth, and establish glia as a model for Merlin-specific Hippo signaling. Moreover, as several of the genes we studied have been linked to human gliomas, our results suggest that this linkage could reflect their organization into a conserved pathway for the control of glial cell proliferation.
Association of Growth Differentiation Factor-15 with Coronary Atherosclerosis and Mortality in a Young, Multiethnic Population: Observations from the Dallas Heart Study
Authors: Rohatgi Anand , Patel Parag , Das Sandeep R , Ayers Colby R , Khera Amit , Martinez-Rumayor Abelardo , Berry Jarett D , McGuire Darren K , de Lemos James A
Published: November 2011

BACKGROUND

Growth differentiation factor 15 (GDF-15) is produced by cardiomyocytes and atherosclerotic lesions under stress conditions. Although higher circulating GDF-15 concentrations are associated with mortality across a spectrum of cardiovascular conditions, the relationship of GDF-15 with atherosclerosis and mortality in the general population remains undefined.

METHODS

We measured plasma GDF-15 in 3219 participants of the Dallas Heart Study, a population sample of adults ages 30–65 years (55% women, 49% black). GDF-15 was analyzed in prespecified categories (<1200; 1200–1799; and ≥1800 ng/L) and continuously. End points included prevalent coronary artery calcium (CAC >10 Agatston units), increased CAC (CAC ≥100 Agatston units) by electron beam computed tomography, and mortality through a median 7.3 years of follow-up (120 deaths, 48 cardiovascular deaths).

RESULTS

Increasing GDF-15 associated with older age, black race, hypertension, diabetes, smoking, left ventricular (LV) mass/body surface area, and worse renal function (P < 0.0001 for each). In multivariable models adjusted for traditional risk factors, renal function, and LV mass/body surface area, GDF-15 ≥1800 ng/L was associated with CAC >10 (odds ratio 2.1; 95% CI 1.2–3.7; P = 0.01), CAC ≥100 (odds ratio 2.6; 95% CI 1.4–4.9; P = 0.002), all-cause mortality (hazard ratio 3.5; 95% CI 2.1–5.9, P < 0.0001), and cardiovascular mortality (hazard ratio 2.5; 95% CI 1.1–5.8, P = 0.03). Adding log GDF-15 to fully adjusted models modestly improved the c statistic (P = 0.025), the integrated discrimination index (0.028; P < 0.0001) and the category-less net reclassification index (0.42; P = 0.002). These findings remained significant with further adjustment for high-sensitivity C-reactive protein, N-terminal pro–B-type natriuretic peptide, and cardiac troponin T.

CONCLUSIONS

GDF-15 is independently associated with subclinical coronary atherosclerosis and mortality, and its potential role for risk stratification in the general population merits further evaluation.
Memory impairment induced by amphetamine derivatives in laboratory animals and in humans: a review
Authors: Camarasa Jordi , Rodrigo Teresa , Pubill David , Escubedo Elena
Published: November 2011

The 20th century brought with it the so-called club drugs (the most notorious being amphetamine derivatives), which are used by young adults at all-night dance parties. Methamphet­amine and 3,4-methylenedioxymethamphetamine (MDMA or ecstasy) are synthetic drugs with stimulant and psychoactive properties that belong to the amphetamine family. Here, we have reviewed the literature about the cognitive impairment induced by these two amphetamine derivatives and the preclinical and clinical outcomes. Although there is controversial evidence about the effect of methamphetamine and MDMA on learning and memory in laboratory animals, results from published papers demonstrate that amphetamines cause long-term impairment of cognitive functions. A large number of pharmacological receptors have been studied and screened as targets of amphetamine-induced cognitive dysfunction, and extensive research efforts have been invested to provide evidence about the molecular mechanisms behind these cognitive deficits. In humans, there is a considerable body of evidence indicating that methamphetamine and MDMA seriously disrupt memory and learning processes. Although an association between the impairments of memory performance and a history of recreational amphetamine ingestion has also been corroborated, a number of methodological difficulties continue to hamper research in this field, the most important being the concomitant use of other illicit drugs.
A Recurrence Related to the Bell Numbers
Authors: Mansour Toufik , Shattuck Mark
Published: November 2011

In this paper, we solve a general, four-parameter recurrence by both algebraic and combinatorial methods. The Bell numbers and some closely related sequences are solutions to the recurrence corresponding to particular choices of the parameters.
Ingenieurtechnische Besonderheiten bei der automatischen Handhabung von biologischen Organismen
Authors: Pylatiuk Christian , Pfriem Alexander , Liebel Urban , Schulz Stefan , Bretthauer Georg
Published: November 2011

Der Zebrabärbling hat sich als Modellorganismus in der Erforschung der Embryonalentwicklung und für toxikologische Untersuchungen etabliert. Automatisches Handhaben und Mikroskopieren von lebenden Objekten ist dabei in allen Prozessschritten nötig. Hierfür wurden in den letzten Jahren verschiedene Roboter entwickelt. Die Einflüsse von abiotischen Stressfaktoren auf die Embryonalentwicklung von Zebrafischen, wie z. B. mechanische Belastungen beim Handhaben oder die Bestrahlung mit hellem Weißlicht während des Mikroskopiervorgangs wurden in der vorliegenden Studie erstmals evaluiert.
DG3173 (somatoprim), a unique somatostatin receptor subtypes 2-, 4- and 5-selective analogue, effectively reduces GH secretion in human GH-secreting pituitary adenomas even in Octreotide non-responsive tumours
Authors: Plöckinger U , Hoffmann U , Geese M , Lupp A , Buchfelder M , Flitsch J , Vajkoczy P , Jakob W , Saeger W , Schulz S , Dohrmann C
Published: November 2011

Objective

Somatostatin analogues (SSA) reduce autonomous GH secretion by activating somatostatin receptors (sst) 2 and 5 in 50–60% of acromegalic patients. However, by inhibiting insulin secretion these SSA reduce glucose tolerance. DG3173 is a novel SSA with additional binding to sst4 and low insulin-suppressing activity. We investigated the effect of DG3173, including its relation to specific tumour characteristics, on GH secretion in human somatotroph adenoma cell cultures (hSA) in comparison with Octreotide.

Methods

Twenty-seven hSA were characterised immunohistochemically for their hormone- and sst-expression, granularity and pre-surgical therapy with SSA. GH was determined in supernatants of hSA treated with DG3173 or Octreotide in time- (n=6) and dose–response (n=21) experiments. A positive response was defined as GH suppression to below 80% of baseline.

Results

In the dose–response experiments DG3173 suppressed GH secretion in more adenomas than Octreotide (10/21 vs 5/21), including 38% (6/16) of Octreotide non-responders. In responders the extent of GH suppression and IC50 were comparable for both SSA. The response-rate of both SSA was higher in monohormonal vs bihormonal adenomas, yet GH declined similarly in both groups. Neither pre-surgical SSA (n=6) nor tumour morphology was related to the GH response. However, semi-quantitative analysis indicated a small but significant negative correlation between the GH response to Octreotide and the immunoreactivity scores of sst2 expression.

Conclusions

DG3173 equalled Octreotide in suppressing GH secretion in hSA. Since DG3173 suppressed GH in some Octreotide-non-responsive adenomas, its clinical effectiveness will be worth testing. Moreover, its reduced insulin-suppressive potency would make it a valuable alternative to Octreotide.
Stress Hyperglycemia: A Sign of Familial Diabetes in Children
Authors: Oron Tal , Gat-Yablonski Galia , Lazar Liora , Phillip Moshe , Gozlan Yael
Published: November 2011

Stress hyperglycemia in children is considered a benign condition that usually does not mandate further investigation. In some clinical settings it might be the first sign of diabetes mellitus (DM). Two unrelated boys, one aged 2 years 7 months and the other aged 5 days, were evaluated in the emergency department for a febrile infection and found to have elevated blood glucose levels (238 and 150 mg/dL [preprandial], respectively). In both cases the elevated hemoglobin A1c levels (6.5% and 6.6%, respectively) combined with a history of gestational DM in the mother and positive family history for DM suggested maturity-onset diabetes of the young. Genetic analysis revealed 2 known heterozygote mutations in the glucokinase gene: c.697T→C p.C233R in the first case and c.616A→C p.T206P in the second case. Our findings suggest that stress hyperglycemia during early childhood in association with a positive family history of DM might be a sign of monogenic diabetes.