Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis

Atopic disease, including atopic dermatitis (eczema), allergy and asthma, has increased in frequency in recent decades and now affects approximately 20% of the population in the developed world. Twin and family studies have shown that predisposition to atopic disease is highly heritable. Although most genetic studies have focused on immunological mechanisms, a primary epithelial barrier defect has been anticipated. Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Here we show that two independent loss-of-function genetic variants (R510X and 2282del4) in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis. These variants are carried by approximately 9% of people of European origin. These variants also show highly significant association with asthma occurring in the context of atopic dermatitis. This work establishes a key role for impaired skin barrier function in the development of atopic disease.     

The PDZ2 domain of zonula occludens-1 and -2 is a phosphoinositide binding domain

Zonula occludens proteins (ZO) are postsynaptic density protein-95 discs large-zonula occludens (PDZ) domain-containing proteins that play a fundamental role in the assembly of tight junctions and establishment of cell polarity. Here, we show that the second PDZ domain of ZO-1 and ZO-2 binds phosphoinositides (PtdInsP) and we identified critical residues involved in the interaction. Furthermore, peptide and PtdInsP binding of ZO PDZ2 domains are mutually exclusive. Although lipid binding does not seem to be required for plasma membrane localisation of ZO-1, phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P ₂) binding to the PDZ2 domain of ZO-2 regulates ZO-2 recruitment to nuclear speckles. Knockdown of ZO-2 expression disrupts speckle morphology, indicating that ZO-2 might play an active role in formation and stabilisation of these subnuclear structures. This study shows for the first time that ZO isoforms bind PtdInsPs and offers an alternative regulatory mechanism for the formation and stabilisation of protein complexes in the nucleus.     

Red blood cells carry out T cell growth and survival bioactivities that are sensitive to cyclosporine A

Red blood cells (RBC) have emerged as a novel regulatory cell type endowed with bioactivities toward activated human T cells. Herein we show that the RBC bioactivities act on intracellular pathways initiated by T cell receptor (TCR)-dependent and -independent stimuli, including IL-2, IL-15, and the mixture of phorbol dibutyrate and ionomycin. The RBC bioactivities preserve the antioxidant status and are capable of rescuing activated T cells from cell death induced by serum deprivation. They are not mediated by glycosylphosphatidylinositol-linked receptors or sialic acids, and kinetic studies revealed that they hasten the entrance into the cell cycle. By using cyclosporine A (CsA) and rapamycin (Rapa) we show that the RBC bioactivities are calcineurin-dependent. Thus, treatment of T cells with CsA, but not Rapa, impaired RBC bioactivities, and preincubation of RBC with CsA completely abolished their bioactivities. We have demonstrated that RBC carry out bioactivities that are sensitive to CsA.     

Yield curve forecast combinations based on bond portfolio performance

We propose an economically motivated forecast combination strategy in which model weights are related to portfolio returns obtained by a given forecast model. An empirical application based on an optimal mean–variance bond portfolio problem is used to highlight the advantages of the proposed approach with respect to combination methods based on statistical measures of forecast accuracy. We compute average net excess returns, standard deviation, and the Sharpe ratio of bond portfolios obtained with nine alternative yield curve specifications, as well as with 12 different forecast combination strategies. Return‐based forecast combination schemes clearly outperformed approaches based on statistical measures of forecast accuracy in terms of economic criteria. Moreover, return‐based approaches that dynamically select only the model with highest weight each period and discard all other models delivered even better results, evidencing not only the advantages of trimming forecast combinations but also the ability of the proposed approach to detect best‐performing models. To analyze the robustness of our results, different levels of risk aversion and a different dataset are considered.     

Do IMF fiscal forecasts add value?

We used a panel of 29 advanced and emerging market countries to investigate whether the IMF's World Economic Outlook (WEO) fiscal forecasts add value in terms of forecast accuracy and information content, relative to private sector forecasts (from Consensus Economics). We find that: (i) WEO forecasts are not significantly less accurate than Consensus forecasts; (ii) WEO and Consensus forecasts tend to mutually encompass one another; and (iii) each source of forecasts appears to contain some information that is not embedded in the other source.     

嵌段聚醚酯化物的结构分析

本文对合成的嵌段聚醚酯化物的分子结构做了红外、高压液相色谱和~(13)C核磁共振分析,得出其构象和各种原子连接的方式,这些特征图谱为研究和生产此类型表面活性剂提供了可靠的检测依据。     

Berthelot's anti-atomism: A ‘matter of taste’?

The influential French chemist Marcelin Berthelot spoke against the use of Dalton's atomic theory and Avogadro's hypothesis in the second half of the nineteenth century. This paper argues that Berthelot conceded that atomism might be acceptable as a system of conventions, but he feared the power of such conventions in constructing a realistic picture of atoms which was not warranted empirically. Equally, Berthelot's anti-atomism was a last-ditch effort to assert the place of chemistry within the tradition of natural history and to deny the possible reduction of chemical science to the laws of nineteenth-century physics.     

Identification and characterization of new functional truncated variants of somatostatin receptor subtype 5 in rodents

Somatostatin and cortistatin exert multiple biological actions through five receptors (sst1-5); however, not all their effects can be explained by activation of sst1-5. Indeed, we recently identified novel truncated but functional human sst5-variants, present in normal and tumoral tissues. In this study, we identified and characterized three novel truncated sst5 variants in mice and one in rats displaying different numbers of transmembrane-domains [TMD; sst5TMD4, sst5TMD2, sst5TMD1 (mouse-variants) and sst5TMD1 (rat-variant)]. These sst5 variants: (1) are functional to mediate ligand-selective-induced variations in [Ca²⁺]_i and cAMP despite being truncated; (2) display preferential intracellular distribution; (3) mostly share full-length sst5 tissue distribution, but exhibit unique differences; (4) are differentially regulated by changes in hormonal/metabolic environment in a tissue- (e.g., central vs. systemic) and ligand-dependent manner. Altogether, our results demonstrate the existence of new truncated sst5-variants with unique ligand-selective signaling properties, which could contribute to further understanding the complex, distinct pathophysiological roles of somatostatin and cortistatin.     

Nonsense suppression therapies in human genetic diseases

Cellular and Molecular Life Sciences - About 11% of all human disease-associated gene lesions are nonsense mutations, resulting in the introduction of an in-frame premature translation-termination...