Global regulatory developments for clinical stem cell research: diversification and challenges to collaborations

In this article, we explore regulatory developments in stem cell medicine in seven jurisdictions: Japan, China, India, Argentina, Brazil, the USA and the EU. We will show that the research methods, ethical standards and approval procedures for the market use of clinical stem cell interventions are undergoing an important process of global diversification. We will discuss the implications of this process for international harmonization and the conduct of multicountry clinical research collaborations. It will become clear that the increasing heterogeneity of research standards and regulations in the stem cell field presents a significant challenge to international clinical trial partnerships, especially with countries that diverge from the regulatory models that have been developed in the USA and the EU

Majoron emitting neutrinoless double beta decay in the electroweak chiral gauge extensions

Fundamental mechanisms for Majoron emitting neutrinoless double beta decay in SU(3)_C x G_W x U(1) models, for electroweak flavor chiral extensions, G_W = SU(3)_L and SU(4)_L are pointed out. Both kinds of known Majoron emitting processes, charged Majoron emitting where the massless Nambu-Goldstone boson itself carries lepton charge, $L=-2$, and the ordinary Majoron emitting where the boson has a small mass are found possible. PACS numbers: 11.15.Ex, 12.60.Fr, 14.80.CpComment: 18 pages, Revtex, 3 Postscript figures. To be published in Phys.Rev.D(1 May 1998

Histomorfología comparada del esófago de dos especies de Arctocephalus: A. australis y A. tropicalis (Mammalia, Carnivora, Pinnipedia, Otariidae).

La estructura del sistema digestivo de los pinnípedos se relaciona directamente con los hábitos alimenticios y la dieta de cada especie. Se estudiaron las características histomorfológicas del esófago de dos otáridos: Arctocephalus australis y Arctocephalus tropicalis, mediante técnicas histológicas convencionales. El esófago consta de cuatro túnicas: mucosa, submucosa, muscular y adventicia/serosa. La mucosa incluye: a) tejido epitelial plano estratificado paracornificado, que en A. tropicalis posee menor cantidad de capas en sus estratos; b) lámina propia de tejido conectivo; c) muscular de la mucosa, de tejido muscular liso, discontinua y de espesor creciente hacia caudal. Existen glándulas acinares en toda su extensión; hacia caudal alcanzan la submucosa. Son más abundantes en A. australis, mientras que forman pequeñas agrupaciones en A. tropicalis. Poseen secreción mucosa, pero en A. tropicalis algunas son mixtas. La submucosa posee tejido conectivo denso irregular. La túnica muscular posee dos capas de tejido muscular estriado esquelético (interna, oblicua/espiralada; externa, longitudinal); hacia caudal la capa interna cambia progresivamente a tejido muscular liso, y la externa continúa con tejido muscular estriado esquelético. Entre ambas existen abundantes vasos y un plexo nervioso mientérico bien desarrollados. La adventicia está muy vascularizada e inervada. Las especies consideradas se alimentan principalmente bajo el agua mientras nadan, mediante la captura de presas que degluten enteras. La musculatura estriada que predomina en casi toda la extensión del órgano, junto con el gran desarrollo glandular, podrían facilitar el pasaje hacia el estómago de un alimento que no es procesado en la cavidad oral. Esto se complementaría con los movimientos corporales multidireccionales (algunos antigravitacionales) que realizan mientras ingieren sus presas. Las diferencias histológicas encontradas podrían atribuirse al tipo de dieta, más generalista en A. tropicalis (cefalópodos, peces y krill), mientras que en A. australis está constituida principalmente por peces, cuyo transporte sería más dificultoso e involucraría mayor fricció

Self-organization with traveling waves: A case for a convective torus

A traveling wave of BaSO4 in the chlorite-thiourea reaction has shown concentric precipitation patterns upon being triggered by the autocatalyst HOCl. The precipitation patterns show circular rings of alternate null and full precipitation regions. This self-organization appears to be the result of the formation of a convective torus. The formation of the convective torus can be described as a Benard-Marangoni instability with lateral heating

Nuclear pairing: new perspectives

Nuclear pairing correlations are known to play an important role in various single-particle and collective aspects of nuclear structure. After the first idea by A. Bohr, B. Mottelson and D. Pines on similarity of nuclear pairing to electron superconductivity, S.T. Belyaev gave a thorough analysis of the manifestations of pairing in complex nuclei. The current revival of interest in nuclear pairing is connected to the shift of modern nuclear physics towards nuclei far from stability; many loosely bound nuclei are particle-stable only due to the pairing. The theoretical methods borrowed from macroscopic superconductivity turn out to be insufficient for finite systems as nuclei, in particular for the cases of weak pairing and proximity of continuum states. We suggest a simple numerical procedure of exact solution of the nuclear pairing problem and discuss the physical features of this complete solution. We show also how the continuum states can be naturally included in the consideration bridging the gap between the structure and reactions. The path from coherent pairing to chaos and thermalization and perspectives of new theoretical approaches based on the full solution of pairing are discussed.Comment: 47 pages, 11 figure

The Human Herpesvirus-7 (HHV-7) U21 Immunoevasin Subverts NK-Mediated Cytoxicity through Modulation of MICA and MICB

Herpesviruses have evolved numerous immune evasion strategies to facilitate establishment of lifelong persistent infections. Many herpesviruses encode gene products devoted to preventing viral antigen presentation as a means of escaping detection by cytotoxic T lymphocytes. The human herpesvirus-7 (HHV-7) U21 gene product, for example, is an immunoevasin that binds to class I major histocompatibility complex molecules and redirects them to the lysosomal compartment. Virus infection can also induce the upregulation of surface ligands that activate NK cells. Accordingly, the herpesviruses have evolved a diverse array of mechanisms to prevent NK cell engagement of NK-activating ligands on virus-infected cells. Here we demonstrate that the HHV-7 U21 gene product interferes with NK recognition. U21 can bind to the NK activating ligand ULBP1 and reroute it to the lysosomal compartment. In addition, U21 downregulates the surface expression of the NK activating ligands MICA and MICB, resulting in a reduction in NK-mediated cytotoxicity. These results suggest that this single viral protein may interfere both with CTL-mediated recognition through the downregulation of class I MHC molecules as well as NK-mediated recognition through downregulation of NK activating ligands

Regulation of immune cell function and differentiation by the NKG2D receptor

NKG2D is one of the most intensively studied immune receptors of the past decade. Its unique binding and signaling properties, expression pattern, and functions have been attracting much interest within the field due to its potent antiviral and anti-tumor properties. As an activating receptor, NKG2D is expressed on cells of the innate and adaptive immune system. It recognizes stress-induced MHC class I-like ligands and acts as a molecular sensor for cells jeopardized by viral infections or DNA damage. Although the activating functions of NKG2D have been well documented, recent analysis of NKG2D-deficient mice suggests that this receptor may have a regulatory role during NK cell development. In this review, we will revisit known aspects of NKG2D functions and present new insights in the proposed influence of this molecule on hematopoietic differentiation

Degradation of cellular mir-27 by a novel, highly abundant viral transcript is important for efficient virus replication in vivo.

Cytomegaloviruses express large amounts of viral miRNAs during lytic infection, yet, they only modestly alter the cellular miRNA profile. The most prominent alteration upon lytic murine cytomegalovirus (MCMV) infection is the rapid degradation of the cellular miR-27a and miR-27b. Here, we report that this regulation is mediated by the ∼1.7 kb spliced and highly abundant MCMV m169 transcript. Specificity to miR-27a/b is mediated by a single, apparently optimized, miRNA binding site located in its 3'-UTR. This site is easily and efficiently retargeted to other cellular and viral miRNAs by target site replacement. Expression of the 3'-UTR of m169 by an adenoviral vector was sufficient to mediate its function, indicating that no other viral factors are essential in this process. Degradation of miR-27a/b was found to be accompanied by 3'-tailing and -trimming. Despite its dramatic effect on miRNA stability, we found this interaction to be mutual, indicating potential regulation of m169 by miR-27a/b. Most interestingly, three mutant viruses no longer able to target miR-27a/b, either due to miRNA target site disruption or target site replacement, showed significant attenuation in multiple organs as early as 4 days post infection, indicating that degradation of miR-27a/b is important for efficient MCMV replication in vivo

Cytomegalovirus microRNAs Facilitate Persistent Virus Infection in Salivary Glands

Micro (mi)RNAs are small non-coding RNAs that regulate the expression of their targets' messenger RNAs through both translational inhibition and regulation of target RNA stability. Recently, a number of viruses, particularly of the herpesvirus family, have been shown to express their own miRNAs to control both viral and cellular transcripts. Although some targets of viral miRNAs are known, their function in a physiologically relevant infection remains to be elucidated. As such, no in vivo phenotype of a viral miRNA knock-out mutant has been described so far. Here, we report on the first functional phenotype of a miRNA knock-out virus in vivo. During subacute infection of a mutant mouse cytomegalovirus lacking two viral miRNAs, virus production is selectively reduced in salivary glands, an organ essential for virus persistence and horizontal transmission. This phenotype depends on several parameters including viral load and mouse genetic background, and is abolished by combined but not single depletion of natural killer (NK) and CD4+ T cells. Together, our results point towards a miRNA-based immunoevasion mechanism important for long-term virus persistence

Comparison of the pathogenesis of the highly passaged MCMV Smith strain with that of the low passaged MCMV HaNa1 isolate in BALB/c mice upon oronasal inoculation

Murine cytomegalovirus (MCMV) Smith strain is widely used in mouse models to study HCMV infections. Due to high serial passages, MCMV Smith has acquired genetic and biological changes. Therefore, a low passaged strain would be more relevant to develop mouse models. Here, the pathogenesis of an infection with MCMV Smith was compared with that of an infection with a low passaged Belgian MCMV isolate HaNa1 in BALB/c adult mice following oronasal inoculation with either a low (10(4) TCID50/mouse) or high (10(6) TCID50/mouse) inoculation dose. Both strains were mainly replicating in nasal mucosa and submandibular glands for one to two months. In nasal mucosa, MCMV was detected earlier and longer (1-49 days post inoculation (dpi)) and reached higher titers with the high inoculation dose compared to the low inoculation dose (14-35 dpi). In submandibular glands, a similar finding was observed (high dose: 7-49 dpi; low dose: 14-42 dpi). In lungs, both strains showed a restricted replication. In spleen, liver and kidneys, only the Smith strain established a productive infection. The infected cells were identified as olfactory neurons and sustentacular cells in olfactory epithelium, macrophages and dendritic cells in NALT, acinar cells in submandibular glands, and macrophages and epithelial cells in lungs for both strains. Antibody analysis demonstrated for both strains that IgG(2a) was the main detectable antibody subclass. Overall, our results show that significant phenotypic differences exist between the two strains. MCMV HaNa1 has been shown to be interesting for use in mouse models in order to get better insights for HCMV infections in immunocompetent humans