Myostatin augments muscle-specific ring finger protein-1 expression through an NF-kB independent mechanism in SMAD3 null muscle.

Smad (Sma and Mad-related protein) 2/3 are downstream signaling molecules for TGF-β and myostatin (Mstn). Recently, Mstn was shown to induce reactive oxygen species (ROS) in skeletal muscle via canonical Smad3, nuclear factor-κB, and TNF-α pathway. However, mice lacking Smad3 display skeletal muscle atrophy due to increased Mstn levels. Hence, our aims were first to investigate whether Mstn induced muscle atrophy in Smad3(-/-) mice by increasing ROS and second to delineate Smad3-independent signaling mechanism for Mstn-induced ROS. Herein we show that Smad3(-/-) mice have increased ROS levels in skeletal muscle, and inactivation of Mstn in these mice partially ablates the oxidative stress. Furthermore, ROS induction by Mstn in Smad3(-/-) muscle was not via nuclear factor-κB (p65) signaling but due to activated p38, ERK MAPK signaling and enhanced IL-6 levels. Consequently, TNF-α, nicotinamide adenine dinucleotide phosphate oxidase, and xanthine oxidase levels were up-regulated, which led to an increase in ROS production in Smad3(-/-) skeletal muscle. The exaggerated ROS in the Smad3(-/-) muscle potentiated binding of C/EBP homology protein transcription factor to MuRF1 promoter, resulting in enhanced MuRF1 levels leading to muscle atrophy.

Heterogeneous 40Ar* distributions in naturally deformed muscovite: in situ UV-laser ablation evidence for micro structurally controlled intragrain diffusion

Micas are commonly used in Ar-40/Ar-39 thermochronological studies of variably deformed rocks yet the physical basis by which deformation may affect radiogenic argon retention in mica is poorly constrained. This study examines the relationship between deformation and deformation-induced microstructures on radiogenic argon retention in muscovite, A combination of furnace step-heating and high-spatial resolution in situ UV-laser ablation Ar-40/Ar-39 analyses are reported for deformed muscovites sampled from a granitic pegmatite vein within the Siviez-Mischabel Nappe, western Swiss Alps (Penninic domain, Brianconnais unit). The pegmatite forms part of the Variscan (similar to 350 Ma) Alpine basement and exhibits a prominent Alpine S-C fabric including numerous mica `fish' that developed under greenschist facies metamorphic conditions, during the dominant Tertiary Alpine tectonic phase of nappe emplacement. Furnace step-heating of milligram quantities of separated muscovite grains yields an Ar-40/Ar-39 age spectrum with two distinct staircase segments but without any statistical plateau, consistent with a previous study from the same area. A single (3 X 5 mm) muscovite porphyroclast (fish) was investigated by in situ UV-laser ablation. A histogram plot of 170 individual Ar-40/Ar-39 UV-laser ablation ages exhibit a range from 115 to 387 Ma with modes at approximately 340 and 260 Ma. A variogram statistical treatment of the (40)Ad/Ar-39 results reveals ages correlated with two directions; a highly correlated direction at 310 degrees and a lesser correlation at 0 degrees relative to the sense of shearing. Using the highly correlated direction a statistically generated (Kriging method) age contour map of the Ar-40/Ar-39 data reveals a series of elongated contours subparallel to the C-surfaces which where formed during Tertiary nappe emplacement. Similar data distributions and slightly younger apparent ages are recognized in a smaller mica fish. The observed intragrain age variations are interpreted to reflect the partial loss of radiogenic argon during Alpine (similar to 35 Ma) greenschist facies metamorphism. One-dirnensional diffusion modelling results are consistent with the idea that the zones of youngest apparent age represent incipient shear band development within the mica porphyroclasts, thus providing a network of fast diffusion pathways. During Alpine greenschist facies metamorphism the incipient shear bands enhanced the intragrain loss of radiogenic argon. The structurally controlled intragrain age variations observed in this investigation imply that deformation has a direct control on the effective length scale for argon diffusion, which is consistent with the heterogeneous nature of deformation. (C) 2001 Elsevier Science B.V. All rights reserved.

Micro-patterning of biomolecules on polymer substrates.

UV−excimer laser photoablation was used, in combination with surface blocking techniques, to pattern proteins on the surfaces of polyimide and poly(ethylene terephthalate). This technique involves physical adsorption of avidin through laser-defined openings in low-temperature laminates or adsorbed protein blocking layers. Visualization of biomolecular patterns were monitored using avidin and fluorescein-labeled biotin as a model receptor−ligand couple. Adsorbed proteins could be shown to bind to UV-laser-treated polymer surfaces up to three times higher than on commercially available polymers. UV-laser photoablation was also used for the generation of three-dimensional structure, which leads to the possibility of biomolecule patterning within polymer-based microanalytical systems. The simplicity and easy handling of the described technique facilitate its application in microdiagnostic devices.

Micro-insurance through corporate-NGO partnerships in West Bengal : opportunities and constraints

This Practical Note examines the nascent micro-insurance sector in West Bengal, paying particular attention to the corporate- NGO partnership model for micro-insurance distribution,which has been enabled by India's unique regulatory framework. We challenge the popularconstruction of this model as a 'win - win' for all parties by analysing conflicting understandings of micro-insurance schemes and their purposes by insurance companies, NGOs, and poorvillagers. The article also considers the role of the specific political context of West Bengal inconstricting corporate- NGO micro-insurance

The meiosis-specific recombinase hDmc1 forms ring structures and interacts with hRad51.

Eukaryotic cells encode two homologs of Escherichia coli RecA protein, Rad51 and Dmc1, which are required for meiotic recombination. Rad51, like E.coli RecA, forms helical nucleoprotein filaments that promote joint molecule and heteroduplex DNA formation. Electron microscopy reveals that the human meiosis-specific recombinase Dmc1 forms ring structures that bind single-stranded (ss) and double-stranded (ds) DNA. The protein binds preferentially to ssDNA tails and gaps in duplex DNA. hDmc1-ssDNA complexes exhibit an irregular, often compacted structure, and promote strand-transfer reactions with homologous duplex DNA. hDmc1 binds duplex DNA with reduced affinity to form nucleoprotein complexes. In contrast to helical RecA/Rad51 filaments, however, Dmc1 filaments are composed of a linear array of stacked protein rings. Consistent with the requirement for two recombinases in meiotic recombination, hDmc1 interacts directly with hRad51.

Diffuse large B-cell lymphoma of Waldeyer's ring has distinct clinicopathologic features: a GELA study.

BACKGROUND: Diffuse large B-cell lymphomas (DLBCLs) arising in specific extranodal sites have peculiar clinicopathologic features. PATIENTS AND METHODS: We analyzed a cohort of 187 primary Waldeyer's ring (WR) DLBCLs retrieved from GELA protocols using anthracyclin-based polychemotherapy. RESULTS: Most patients (92%) had stage I-II disease. A germinal center B-cell-like (GCB) immunophenotype was observed in 61%, and BCL2 expression in 55%, of WR DLBCLs. BCL2, BCL6, IRF4 and MYC breakpoints were observed in, respectively, 3 of 42 (7%), 9 of 36 (25%), 2 of 26 (8%) and 4 of 40 (10%) contributive cases. A variable follicular pattern was evidenced in 30 of 68 (44%) large biopsy specimens. The 5-year progression-free survival (PFS) and the overall survival (OS) of 153 WR DLBCL patients with survival information were 69.5% and 77.8%, respectively. The GCB immunophenotype correlated with a better OS (P = 0.0015), while BCL2 expression predicted a worse OS (P = 0.037), an effect overcome by the GCB/non-GCB classification. Compared with matched nodal DLBCLs, WR DLBCLs with no age-adjusted international prognostic index factor disclosed a better 5-year PFS rate (77.5% versus 70.7%; P = 0.03). CONCLUSIONS: WR DLBCLs display distinct clinicopathologic features compared with conventional DLBCLs, with usual localized-stage disease, common follicular features and a high frequency of GCB immunophenotype contrasting with a low rate of BCL2 rearrangements. In addition, they seem to be associated with a better outcome than their nodal counterpart.

An unusual uterine tumour with signet ring cell features

Objective: Lymphomas with signet ring cell features are rare, as is uterine dissemination of lymphomas. We report an exceptional case of a uterine tumor combining these two characteristics. Method: A 61-year-old female was diagnosed in 2004 with localized nodal grade 2 follicular lymphoma (stage IA). She received local radiation therapy, experienced total remission, and did well until 2009 when a systematic CT scan evidenced a pelvic anterior-lateral mass. Total enlarged hysterectomy was performed. Results: The anterior uterine wall contained a 4.8-cm fish flesh well-delineated mass corresponding to a mostly diffuse and focally nodular proliferation of medium to large cells with extensive signet ring cell changes. Tumor cells were CD20-, CD10-, Bcl2-, and Bcl6-positive with a low proliferation rate (<10-15%); CD21 underlined a focal follicular architecture. The vacuoles were PAS-negative and did not stain for immunoglobulin; ultrastructural analysis revealed nonspecific degenerative vacuoles. No lymph nodes were identified isolated from the surgical specimen. The tumor was considered as a secondary localization of the systemic follicular lymphoma, though no signet ring cells were evidenced in the cervical lymph node biopsy (reviewed). Follow-up showed retroperitoneal tissue infiltration (PET-CT) and normal medullar biopsy. She recently started R-CHOP chemotherapy. Conclusion: This case illustrates both an unusual site of dissemination and challenging cytological characteristics in a follicular lymphoma. The signet ring cell changes challenged the adequate classification of this lymphoma as either a large B cell or a follicular B cell lymphoma.

Analysis of micro- and nano-structures of the corneal surface of Drosophila and its mutants by atomic force microscopy and optical diffraction.

Drosophila melanogaster is a model organism instrumental for numerous biological studies. The compound eye of this insect consists of some eight hundred individual ommatidia or facets, ca. 15 µm in cross-section. Each ommatidium contains eighteen cells including four cone cells secreting the lens material (cornea). High-resolution imaging of the cornea of different insects has demonstrated that each lens is covered by the nipple arrays--small outgrowths of ca. 200 nm in diameter. Here we for the first time utilize atomic force microscopy (AFM) to investigate nipple arrays of the Drosophila lens, achieving an unprecedented visualization of the architecture of these nanostructures. We find by Fourier analysis that the nipple arrays of Drosophila are disordered, and that the seemingly ordered appearance is a consequence of dense packing of the nipples. In contrast, Fourier analysis confirms the visibly ordered nature of the eye microstructures--the individual lenses. This is different in the frizzled mutants of Drosophila, where both Fourier analysis and optical imaging detect disorder in lens packing. AFM reveals intercalations of the lens material between individual lenses in frizzled mutants, providing explanation for this disorder. In contrast, nanostructures of the mutant lens show the same organization as in wild-type flies. Thus, frizzled mutants display abnormal organization of the corneal micro-, but not nano-structures. At the same time, nipples of the mutant flies are shorter than those of the wild-type. We also analyze corneal surface of glossy-appearing eyes overexpressing Wingless--the lipoprotein ligand of Frizzled receptors, and find the catastrophic aberration in nipple arrays, providing experimental evidence in favor of the major anti-reflective function of these insect eye nanostructures. The combination of the easily tractable genetic model organism and robust AFM analysis represents a novel methodology to analyze development and architecture of these surface formations.

Off-pump transapical mitral valve-in-ring implantation.

OBJECTIVES: The study aimed to evaluate the feasibility of off-pump transapical mitral valve-in-ring implantation and to test the performance of a custom-made self-expandable stent valve, in comparison with the standard SAPIEN valve. METHODS: Acute experiments were performed in five pigs. Animals (mean weight 58.4 ± 7.3 kg) underwent mitral valve annuloplasties under cardiopulmonary bypass using 26-mm rings (SJM?). Then, a 30-mm custom-made self-expandable stent valve or a 23-mm balloon-expandable transcatheter heart valve (Edwards SAPIEN XT?) was deployed within the annuloplasty rings through a transatrial access and under direct vision. Subsequently, the stent valves were inserted transapically under fluoroscopic guidance and off pump. RESULTS: The procedural success of transatrial and transapical mitral valve-in-ring procedures was 100% (10 of 10). Mean transatrial and transapical procedure time was 2.0 ± 1.1 and 22.0 ± 5.7 min, respectively. Haemodynamic status during transapical implantation remained stable, and differences in data collected before and after the stent-valve deployment were not statistically significant. Mean mitral annulus diameter and mean mitral orifice area in the group of self-expandable stent valves were 2.60 ± 0.02 cm and 4.16 ± 0.48 cm(2), respectively, whereas in the SAPIEN group they were 1.95 ± 0.18 cm and 2.26 ± 0.20 cm(2), respectively. Trace or mild regurgitation was detected only in the self-expandable stent-valve group. Mean gradients were 4.1 ± 4.5 mmHg across the self-expandable stent valves and 1.0 ± 0 mmHg across the SAPIEN valves. Postmortem examination confirmed adequate positioning of the self-expandable valves and the SAPIEN valves within the annuloplasty ring. CONCLUSIONS: Off-pump transapical mitral valve-in-ring implantation is safe and feasible. Transapical access may represent the ideal option for valve-in-ring procedures in cases of recurrent mitral regurgitation after mitral valve repair, in high-risk patients. Owing to the supra-annular profile of the valve components, our custom-made nitinol stent valve provides nearer to normal functional area than the SAPIEN valve.

Komik, Ernst und Mise en page. Zum Problem der Farblinien in Heinrich Wittenwilers "Der Ring"

Der Aufsatz nähert sich dem Interpretationsproblem des ,Ring', eines seit Forschungsbeginn ausserordentlich konträr diskutierten Textes, aus wissenschaftsanalytischer Perspektive. Er führt die Zersplitterung und die Extremisierung der Deutungsansätze, die die breite Forschung zu Wittenwilers Werk kennzeichnet, auf einen vergleichsweise simplen Befund zurück: die ungeklärte Frage nach dem Verhältnis von Komik und Didaktik und der Ernsthaftigkeit des lehrhaften Angebots im ,Ring'. Die so auf grundlegendster Ebene offen gebliebene Erfassung des Textes führt in einen interpretatorischen Leerraum, in dem die widersprüchlichsten, oft wissenschaftsideologisch begründeten Positionen Platz finden. Ihre Analyse zeigt, dass sie sich in wiederkehrende Gruppierungen ordnen. Als Schlüsselglied sowohl der Befunddaten als auch der konträren Vernetzungen von Befund und Deutung wird die wechselnd rote und grüne Initialenlinie der Münchner Handschrift identifiziert. Als im Prolog eingeführte Markierung von Ernst auf der einen und Komik auf der anderen Seite ist sie nicht nur visueller Ausdruck des Deutungsproblems des ,Ring', sondern sie hat es wegen der scheinbaren Unstimmigkeit ihrer Zuweisungen auch wesentlich bedingt. Der Aufsatz zeigt ihren bisher übersehenen Aufschluss für das Verständnis des Werks. Nimmt man die Linie als graphisches Verfahren ernst, stellt sie sich als strukturelle Markierung zum Auffinden von Text im diskontinuierlichen Zugriff dar - nicht aber, wie man sie bisher ausnahmslos verstand, als semantische Kommentierung eines laufenden, kontinuierlich zu lesenden Textes. Die strukturierende Funktion des Farbwechsels ist auf zwei Ebenen nachzuweisen: Auf Makroebene trennen seine Zuweisungen vorwiegend narrative und vorwiegend wissensvermittelnde Grosspartien des ,Ring' durch eine jeweilige Grundfarbe. Auf Mikroebene wird diese Grundfarbe durch die jeweils andere Farbe durchbrochen, um formale Einschnitte wie etwa Sprecherwechsel, Ortswechsel, Handlungsneueinsätze, Beginn und Ende eines eingeschalteten Binnentextes oder einer Sentenz anzuzeigen. Dem Benutzer der autornahen Handschrift sollte so in einem ersten Schritt (makrostrukturell) ermöglicht werden, gezielt auf gewünschte Stellen des Textes zuzugreifen und ihn in einem zweiten Schritt (mikrostrukturell) schneller zu erfassen. Nicht in seiner Umsetzung, sehr wohl aber in seiner Funktion steht dieses ungewöhnliche Layout zeitgenössischen Techniken der Buchgliederung durchaus nahe. Auch im Profil der Zusammenstellung seiner Binnentexte rückt der ,Ring' damit in die Nähe der im Spätmittelalter beliebten Sammelhandschriften mit Ziel einer Wissenssumme, die hier narrativ verbundenen wird. Es scheint, als möchte der ,Ring' in einem ungewöhnlichen Experiment beides sein: Kompilation und Werkganzes, Wissenssammlung und Erzählwerk - Texte und Text. Als Ergebnis einer Neuuntersuchung des Münchner codex unicus des ,Ring' weist der Beitrag schliesslich darauf hin, dass auch zahlreiche Markierungszeichen am Spaltenrand formale und strukturelle Texteinschnitte anzeigen und somit die gleiche Funktion haben wie der Farbwechsel auf Mikroebene. Ein kausaler, produktionstechnischer Zusammenhang zwischen diesen Zeichen und der Verteilung des Farbwechsels ist nicht auszuschliessen, zumal beide Verfahren etwa im letzten Fünftel des Textes zunehmend zusammenfallen. Möglicherweise war nur die makrostrukturelle Funktion des Farbwechsel ursprünglich indendiert und mit der Erläuterung im Prolog bezeichnet, während seine mikrostrukturelle Funktion erst Resultat des Abschreibprozesses ist.

Tumor cell budding and laminin-5 expression in colorectal carcinoma can be modulated by the tissue micro-environment.

Expression of laminin-5 alpha3, beta3 and gamma2 protein subunits was investigated in colorectal adenocarcinomas using immunostaining and confocal microscopy. The laminin-5 heterotrimer was found in basement membranes and as extracellular deposits in tumor stroma. In contrast to the alpha3 subunit, which was under-expressed, the gamma2 and beta3 subunits were detected in the cytoplasm of carcinoma cells dissociating (budding) from neoplastic tubules, suggestive of focal alterations in laminin-5 assembly and secretion. Laminin-5 gamma2 or beta3 subunit-reactive budding carcinoma cells expressed cytokeratins but not vimentin; they did not proliferate and were not apoptotic. Furthermore, expression of laminin-5 gamma2 and beta3 subunits in budding cells was associated with focal under-expression of the E-cadherin-beta-catenin complex. Results from xenograft experiments showed that budding activity in colorectal adenocarcinomas could be suppressed when these tumors grew at ectopic s.c. sites in nude mice. In vitro, cultured colon carcinoma cells, but not adenoma-derived tumor cells, shared the laminin-5 phenotype expressed by carcinoma cells in vivo. Using colon carcinoma cell lines implanted orthotopically and invading the cecum of nude mice, the laminin-5-associated budding was restored, indicating that this phenotype is not only determined by tumor cell properties but also dependent on the tissue micro-environment. Our results indicate that both laminin-5 alpha3 subunit expression and cell-cell cohesiveness are altered in budding carcinoma cells, which we consider to be actively invading. We propose that the local tissue micro-environment contributes to these events.