Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia.

No treatment for frontotemporal dementia (FTD), the second most common type of early-onset dementia, is available, but therapeutics are being investigated to target the 2 main proteins associated with FTD pathological subtypes: TDP-43 (FTLD-TDP) and tau (FTLD-tau). Testing potential therapies in clinical trials is hampered by our inability to distinguish between patients with FTLD-TDP and FTLD-tau. Therefore, we evaluated truncated stathmin-2 (STMN2) as a proxy of TDP-43 pathology, given the reports that TDP-43 dysfunction causes truncated STMN2 accumulation. Truncated STMN2 accumulated in human induced pluripotent stem cell-derived neurons depleted of TDP-43, but not in those with pathogenic TARDBP mutations in the absence of TDP-43 aggregation or loss of nuclear protein. In RNA-Seq analyses of human brain samples from the NYGC ALS cohort, truncated STMN2 RNA was confined to tissues and disease subtypes marked by TDP-43 inclusions. Last, we validated that truncated STMN2 RNA was elevated in the frontal cortex of a cohort of patients with FTLD-TDP but not in controls or patients with progressive supranuclear palsy, a type of FTLD-tau. Further, in patients with FTLD-TDP, we observed significant associations of truncated STMN2 RNA with phosphorylated TDP-43 levels and an earlier age of disease onset. Overall, our data uncovered truncated STMN2 as a marker for TDP-43 dysfunction in FTD

Cachimbos europeus de cerâmica branca, séculos XVI ao XIX: parâmetros básicos para análise arqueológica

O tabaco foi introduzido na Europa no final do século XV. Desde então, uma das formas mais comuns para o seu consumo foi o cachimbo, além do rapé, do tabaco de mascar, do charuto e, mais recentemente, dos cigarros. Os cachimbos de cerâmica branca, largamente produzidos e utilizados na Europa desde o século XV, são encontrados em sítios arqueológicos históricos ao redor do mundo, incluindo no Brasil, em decorrência do comércio internacional, que gradualmente se intensificou após o início da conquista europeia. Eles funcionam como excelentes elementos para datação de sítios e estratos arqueológicos, tendo sido estudados em vários países a partir dessa abordagem. Ainda, esse tipo de artefato, mais que fornecer datações, permite identificar redes comerciais entre nações e desenvolver discussões de cunho social e cultural. Contudo, eles foram pouco estudados no Brasil. Visando contribuir com os estudos nacionais dessa categoria material, este artigo oferece uma revisão da literatura internacional acerca do histórico da produção dos cachimbos europeus de caulim, incluindo apresentação dos principais centros produtores; da morfologia e decoração desses produtos, considerando a cronologia do fabrico; e dos métodos de análise dos diferentes cachimbos de caulim no âmbito da arqueologia histórica.Tobacco was introduced in Europe at the end of the 15th century. Since then, one of the most traditional means for its use has been the pipe, next to the powder version, chewing, cigars, and, more recently, cigarettes. White clay tobacco pipes, widely produced and used in Europe since the 15th century, are found in historical archaeological sites around the world, including Brazil, due to international trade, which gradually intensified with the European conquest of the New World. They are excellent guides for dating archaeological sites and layers. In addition, this type of artifact, more than a dating tool, permits identifying trading networks between nations and developing discussions of cultural and social nature. These pipes, however, have been understudied in Brazil. In order to contribute to studies of this type of artifact in our country, this paper offers a revision of the international literature on the history of clay pipe production in Europe, including the presentation of main production centers; morphology and decoration of these products, considering issues of fabrication chronology; and the methods used in Historical Archaeology for analyzing clay tobacco pipes

The FRIABLE1 Gene Product Affects Cell Adhesion in Arabidopsis

Cell adhesion in plants is mediated predominantly by pectins, a group of complex cell wall associated polysaccharides. An Arabidopsis mutant, friable1 (frb1), was identified through a screen of T-DNA insertion lines that exhibited defective cell adhesion. Interestingly, the frb1 plants displayed both cell and organ dissociations and also ectopic defects in organ separation. The FRB1 gene encodes a Golgi-localized, plant specific protein with only weak sequence similarities to known proteins (DUF246). Unlike other cell adhesion deficient mutants, frb1 mutants do not have reduced levels of adhesion related cell wall polymers, such as pectins. Instead, FRB1 affects the abundance of galactose- and arabinose-containing oligosaccharides in the Golgi. Furthermore, frb1 mutants displayed alteration in pectin methylesterification, cell wall associated extensins and xyloglucan microstructure. We propose that abnormal FRB1 action has pleiotropic consequences on wall architecture, affecting both the extensin and pectin matrices, with consequent changes to the biomechanical properties of the wall and middle lamella, thereby influencing cell-cell adhesion

Comparison of pectin methylesterase (PME) activity in <i>FRB1</i> and <i>frb1</i> alleles and analysis of esterified and non-esterified cell wall regions using FTIR.

<p>A. PME activity in <i>frb1</i> alleles is from 45–70% higher than in wild-type seedlings. Degree of methylesterification of the pectin used as substrate in PME assays is indicated as percentage. Each column is the average of three separate assays; error bars indicate ± standard deviation. All levels are significantly different with p<0.05 for all three <i>frb1</i> lines compared to wild-type B. Comparison of <i>FRB1</i> and <i>frb1</i> of FTIR scans. C. Close-up of region III from A. showing particular differences in the degree of methylesterification between <i>FRB1</i> and <i>frb1</i>.</p

Phenotypic variation in <i>frb1</i> mutant seedlings.

<p>A. Wild-type <i>FRB1</i> seedling after 5 days growth on MS media. B. A 3-day old <i>frb1–1</i> seedling where the hypocotyl has spontaneously broken during germination. C. An example of a <i>frb1–1</i> seedling where the cotyledons have become fused as the seedling germinated. D. A <i>frb1–2</i> seedling showing severe cell dissociation. E. A two week old <i>FRB1</i> seedling grown on MS media. F. and G. At the same stage of growth as seedlings in E, <i>frb1–1</i> and <i>frb1–2</i> seedlings have little cell separation but many do have extensive fusions between leaves and other aerial organs. All scale bars equal 0.5. mm.</p

Sugar composition and sugar incorporation in membrane preparations from <i>FRB1</i> and <i>frb1</i> plants.

<p>A. Sugar composition derived from microsomal preparations of wild-type and <i>frb1</i>–<i>2</i>. Monosaccharides and uronic acids were identified based on retention time and comparison to pure standards and values are expressed in % of total area. Significant changes (two-tailed Student's t-test, n = 3, *: p<0.05; **: p<0.01) are marked with stars. Rha: rhamnose, Ara: arabinose, Gal: galacatose, Glc: glucose, Xyl-Man: unseparated peak containing xylose and mannose, GalA: galacturonic acid, GlcA: glucuronic acid. B. The total radioactivity in the chloroform insoluble material. C. The total radioactivity in the chloroform soluble material. See the experimental procedures for details.</p

Annotation of cell wall genes upregulated in <i>frb1</i> and immunolabeling of transverse hypocotyl sections using antibodies against arabinosylated cell wall epitopes.

<p>A. Differentially expressed genes involved in cell wall metabolism. Increase of expression of in <i>frb1</i> upregulated cell wall genes with n = 3. Error bars are ± standard deviation. B. to K. Immunolabeling of transverse hypocotyl sections (10 µm) using antibodies against arabinosyl epitopes predominantly present in extensins (LM1; D to G) or in RGI side chains (LM6; H to K). B. <i>FRB1</i> anti-rat control. C. <i>frb1–1</i> anti-rat control. D. and E. <i>FRB1</i> staining using LM1. F. and G. <i>frb1–1</i> staining using LM1. H. and I. <i>FRB1</i> staining using LM6. J. and K. <i>frb1–1</i> staining using LM6. Scale bars in B, C, D, F, H, J equal 50 µm, scale bars in E, G, I, K equal 25 µm.</p