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Cardiac ATTR amyloidosis, a serious but much under-diagnosed form of cardiomyopathy, is caused by deposition of amyloid fibrils derived from the plasma protein transthyretin (TTR), but its pathogenesis is poorly understood and informative in vivo models have proved elusive. Here we report the generation of a mouse model of cardiac ATTR amyloidosis with transgenic expression of human TTR S52P . The model is characterised by substantial ATTR amyloid deposits in the heart and tongue. The amyloid fibrils contain both full-length human TTR protomers and the residue 49-127 cleavage fragment which are present in ATTR amyloidosis patients. Urokinase-type plasminogen activator (uPA) and plasmin are abundant within the cardiac and lingual amyloid deposits, which contain marked serine protease activity; knockout of α 2 -antiplasmin, the physiological inhibitor of plasmin, enhances amyloid formation. Together, these findings indicate that cardiac ATTR amyloid deposition involves local uPA-mediated generation of plasmin and cleavage of TTR, consistent with the previously described mechano-enzymatic hypothesis for cardiac ATTR amyloid formation. This experimental model of ATTR cardiomyopathy has potential to allow further investigations of the factors that influence human ATTR amyloid deposition and the development of new treatments. ATTR amyloidosis causes heart failure through the accumulation of misfolded transthyretin in cardiac muscle. Here the authors report a mouse model of ATTR amyloidosis and demonstrate the involvement of protease activity in ATTR amyloid deposition.

Antibody-Associated Cardiac Amyloid RegressionThe investigators describe antibodies that bound amyloid in three patients with transthyretin amyloidosis. Spontaneous regression of cardiomyopathy occurred in all three patients.

In this study, the combined effect of graphene oxide (GO) and oxidized multi-walled carbon nanotubes (OMWCNTs) on material properties of the magnesium oxychloride (MOC) phase 5 was analyzed. The selected carbon-based nanoadditives were used in small content in order to obtain higher values of mechanical parameters and higher water resistance while maintaining acceptable price of the final composites. Two sets of samples containing either 0.1 wt. % or 0.2 wt. % of both nanoadditives were prepared, in addition to a set of reference samples without additives. Samples were characterized by X-ray diffraction, scanning electron microscopy, Fourier-transform infrared spectroscopy, and energy dispersive spectroscopy, which were used to obtain the basic information on the phase and chemical composition, as well as the microstructure and morphology. Basic macro- and micro-structural parameters were studied in order to determine the effect of the nanoadditives on the open porosity, bulk and specific density. In addition, the mechanical, hygric and thermal parameters of the prepared nano-doped composites were acquired and compared to the reference sample. An enhancement of all the mentioned types of parameters was observed. This can be assigned to the drop in porosity when GO and OMWCNTs were used. This research shows a pathway of increasing the water resistance of MOC-based composites, which is an important step in the development of the new generation of construction materials.

Common variable immunodeficiency (CVID) is a heterogeneous group of diseases. Our aim was to define sub-groups of CVID patients with similar phenotypes and clinical characteristics. Using eight-color flow cytometry, we analyzed both B- and T-cell phenotypes in a cohort of 88 CVID patients and 48 healthy donors. A hierarchical clustering of probability binning “bins” yielded a separate cluster of 22 CVID patients with an abnormal phenotype. We showed coordinated proportional changes in naïve CD4+ T-cells (decreased), intermediate CD27− CD28+ CD4+ T-cells (increased) and CD21low B-cells (increased) that were stable for over three years. Moreover, the lymphocytes’ immunophenotype in this patient cluster exhibited features of profound immunosenescence and chronic activation. Thrombocytopenia was only found in this cluster (36% of cases, manifested as Immune Thrombocytopenia (ITP) or Evans syndrome). Clinical complications more frequently found in these patients include lung fibrosis (in 59% of cases) and bronchiectasis (55%). The degree of severity of these symptoms corresponded to more deviation from normal levels with respect to CD21low B-cells, naïve CD4+ and CD27− CD28+ CD4+ T-cells. Next-generation sequencing did not reveal any common genetic background. We delineate a subgroup of CVID patients with activated and immunosenescent immunophenotype of lymphocytes and distinct set of clinical complications without common genetic background.

The uptake and metabolism of trans -zeatin and/or dihydrozeatin, in correlation with cytokinin oxidase/dehydrogenase (CKX) and β-glucosidase activity, were studied in leaf segments derived from wild-type (WT) and transgenic (T) tobacco ( Nicotiana tabacum L. cv. Petit Havana SR1) during in vitro induction of shoot organogenesis. T explants harbored the maize gene Zm - p60.1 β- glucosidase . Higher levels of shoot regeneration were observed on T explants in the early stages of cultivation. In WT explants, the content of cytokinin (CK)- O - and N -glucosides increased. In T explants, a higher content of Z-9-riboside and Z-9-riboside-5′-monophosphate and higher CKX activity during the early stage of cultures were found. A positive correlation was obtained for bioactive CK content and the organogenic response in T explants. Our results indicate a connection between the organogenic capacity of tobacco explants, metabolism of endogenous CKs and uptake of exogenous CKs from the cultivation medium.

Scientific Reports 7: Article number: 39710; published online: 05 January 2017; updated: 27 February 2017. The original version of this Article contained errors in the Abstract. “The degree of severity of these symptoms corresponded to more deviation from normal levels with respect to CD21low B-cells, naïve CD4+ and CD27− CD28+ over three years.