Systematic Review: Drug Repositioning for Congenital Disorders of Glycosylation (CDG)

Advances in research have boosted therapy development for congenital disorders of glycosylation (CDG), a group of rare genetic disorders affecting protein and lipid glycosylation and glycosylphosphatidylinositol anchor biosynthesis. The (re)use of known drugs for novel medical purposes, known as drug repositioning, is growing for both common and rare disorders. The latest innovation concerns the rational search for repositioned molecules which also benefits from artificial intelligence (AI). Compared to traditional methods, drug repositioning accelerates the overall drug discovery process while saving costs. This is particularly valuable for rare diseases. AI tools have proven their worth in diagnosis, in disease classification and characterization, and ultimately in therapy discovery in rare diseases. The availability of biomarkers and reliable disease models is critical for research and development of new drugs, especially for rare and heterogeneous diseases such as CDG. This work reviews the literature related to repositioned drugs for CDG, discovered by serendipity or through a systemic approach. Recent advances in biomarkers and disease models are also outlined as well as stakeholders’ views on AI for therapy discovery in CDG.     

Adipose Tissue Dysfunction and Obesity-Related Male Hypogonadism

Obesity is a chronic illness associated with several metabolic derangements and comorbidities (i.e., insulin resistance, leptin resistance, diabetes, etc.) and often leads to impaired testicular function and male subfertility. Several mechanisms may indeed negatively affect the hypothalamic–pituitary–gonadal health, such as higher testosterone conversion to estradiol by aromatase activity in the adipose tissue, increased ROS production, and the release of several endocrine molecules affecting the hypothalamus–pituitary–testis axis by both direct and indirect mechanisms. In addition, androgen deficiency could further accelerate adipose tissue expansion and therefore exacerbate obesity, which in turn enhances hypogonadism, thus inducing a vicious cycle. Based on these considerations, we propose an overview on the relationship of adipose tissue dysfunction and male hypogonadism, highlighting the main biological pathways involved and the current therapeutic options to counteract this condition.     

Immunocytochemical study of alpha 1 and beta 2/3 subunits of GABAA receptors in freehand isolated vestibular Deiters' neurons

Vestibular Deiters' neurons have been isolated from bovine brain by the Hydén's freehand dissection technique and challenged with monoclonal antibodies directed toward the alpha 1 and beta 2/3 subunits of the GABAA receptors. Subsequent challenge with fluorescent secondary antibodies and confocal microscopy allowed the study of the cellular distribution of such subunits. In Deiters' neurons the beta 2/3 subunit displayed a clear presence all along the cell body profile and the initial parts of the dendrites. The alpha 1 subunit was found highly present all over the cell interior except the nuclear profiles. The strong presence inside the cells possibly masked its presence on the plasma membrane. However, in part of the cells studied a distinct presence on the plasma membrane was evident. This subunit was visualized also all along the long dendrites of these neurons. The approach we describe here, involving freehand isolated mature neurons from adult animals, may allow a better characterization of the tridimensional distribution of different types of neuronal GABAA receptors in the respect of the approach with brain slices.     

3G与换机将引爆亚太区手机市场

对于终端厂商而言,亚太区是全球最大的市场,并且潜力最大,因为这一地区拥有全球40%的移动用户。随着欧洲和北美等成熟市场增长趋缓,亚太区的重要性正日渐提升。在那些收入存在较大差距的地区,现阶段运营商面临的挑战是既要鼓励高端用户使用数据业务,又要吸引低收入人群入网而对于设备商而言,则必须在保持现有利润水平的前提下为运营商和消费者提供丰富多彩的终端。无论是运营商、终端提供商还是应用开发商在制定战略时都必须对未来的终端技术有一个清楚的认识。与西欧所有运营商只采用GSM和WCDMA不同的是,亚太地区正在或计划使用的技术…     

No Shades of Gray: The Binary Discourse of George W. Bush and an Echoing Press

Binary communications represent the world as a place of polar opposites. Such conceptions of reality, although not uncommon in Western thought, take on a heightened importance when political leaders employ them in a concerted, strategic discourse in a mass media environment. With this in mind, this research offers a conception of binary discourse and uses this as a foundation to examine (a) the use of binaries by U.S. President George W. Bush in 15 national addresses, from his inauguration in January 2001 to commencement of the Iraq War in March 2003, and (b) the responses of editorials in 20 leading U.S. newspapers to the president's communications.     

Effect of Drought and Methyl Jasmonate Treatment on Primary and Secondary Isoprenoid Metabolites Derived from the MEP Pathway in the White Spruce Picea glauca

White spruce (Picea glauca) emits monoterpenes that function as defensive signals and weapons after herbivore attack. We assessed the effects of drought and methyl jasmonate (MeJA) treatment, used as a proxy for herbivory, on monoterpenes and other isoprenoids in P. glauca. The emission of monoterpenes was significantly increased after MeJA treatment compared to the control, but drought suppressed the MeJA-induced increase. The composition of the emitted blend was altered strongly by stress, with drought increasing the proportion of oxygenated compounds and MeJA increasing the proportion of induced compounds such as linalool and (E)-β-ocimene. In contrast, no treatment had any significant effect on the levels of stored monoterpenes and diterpenes. Among other MEP pathway-derived isoprenoids, MeJA treatment decreased chlorophyll levels by 40%, but had no effect on carotenoids, while drought stress had no impact on either of these pigment classes. Of the three described spruce genes encoding 1-deoxy-D-xylulose-5-phosphate synthase (DXS) catalyzing the first step of the MEP pathway, the expression of only one, DXS2B, was affected by our treatments, being increased by MeJA and decreased by drought. These findings show the sensitivity of monoterpene emission to biotic and abiotic stress regimes, and the mediation of the response by DXS genes.     

The Effect of Ionic Surfactant Adsorption on the Rheology of Ceramic Glaze Suspensions

The rheological behavior of ceramic glaze suspensions containing limestone, quartz, feldspar, and kaolin, has been improved by the addition of either a cationic (cetylpyridinium chloride, CPC) or an anionic (sodium dodecylbenzenesulfonate, SDBS) surfactant. Additional stability and lower viscosity can result from either electrical double layer repulsion or steric repulsion depending on the surfactant type, concentration, ionic strength, and pH. Underdosing may result in high viscosity due to charge neutrality and hydrophobic attraction between particles while overdosing may result in high viscosity possibly due to micelles in the solution. The situation is particularly complicated for glazes containing limestone and anionic surfactant at moderate to low pH where calcium carbonate is soluble. The anionic surfactant and calcium ions can form complexes that are poorly soluble and strongly adsorb to the surface of the particles. The resulting thick steric layer of complexes produces a significant repulsion and stable, low viscosity suspensions. ζ potential measurements and adsorption isotherms are used to interpret the rheological behavior.