Rare missense variants in Tropomyosin-4 (TPM4) are associated with platelet dysfunction, cytoskeletal defects, and excessive bleeding

Background: A significant challenge is faced for the genetic diagnosis of inherited platelet disorders in which candidate genetic variants can be found in more than 100 bleeding, thrombotic, and platelet disorder genes, especially within families in which there are both normal and low platelet counts. Genetic variants of unknown clinical significance (VUS) are found in a significant proportion of such patients in which functional studies are required to prove pathogenicity. Objective: To identify the genetic cause in patients with a suspected platelet disorder and subsequently perform a detailed functional analysis of the candidate genetic variants found. Methods: Genetic and functional studies were undertaken in three patients in two unrelated families with a suspected platelet disorder and excessive bleeding. A targeted gene panel of previously known bleeding and platelet genes was used to identify plausible genetic variants. Deep platelet phenotyping was performed using platelet spreading analysis, transmission electron microscopy, immunofluorescence, and platelet function testing using lumiaggregometry and flow cytometry. Results: We report rare conserved missense variants (p.R182C and p.A183V) in TPM4 encoding tromomyosin-4 in 3 patients. Deep platelet phenotyping studies revealed similar platelet function defects across the 3 patients including reduced platelet secretion, and aggregation and spreading defects suggesting that TPM4 missense variants impact platelet function and show a disordered pattern of tropomyosin staining. Conclusions: Genetic and functional TPM4 defects are reported making TPM4 a diagnostic grade tier 1 gene and highlights the importance of including TPM4 in diagnostic genetic screening for patients with significant bleeding and undiagnosed platelet disorders, particularly for those with a normal platelet count

Complex windmill transformation producing new purely magnetic fluids

Minimal complex windmill transformations of G2IB(ii) spacetimes (admitting a two-dimensional Abelian group of motions of the so-called Wainwright B(ii) class) are defined and the compatibility with a purely magnetic Weyl tensor is investigated. It is shown that the transformed spacetimes cannot be perfect fluids or purely magnetic Einstein spaces. We then determine which purely magnetic perfect fluids (PMpfs) can be windmill-transformed into purely magnetic anisotropic fluids (PMafs). Assuming separation of variables, complete integration produces two, algebraically general, G2I-B(ii) PMpfs: a solution with zero 4-acceleration vector and spatial energy–density gradient, previously found by the authors, and a new solution in terms of Kummer's functions, where these vectors are aligned and non-zero. The associated windmill PMafs are rotating but non-expanding. Finally, an attempt to relate the spacetimes to each other by a simple procedure leads to a G2I-B(ii) one-parameter PMaf generalization of the previously found metric

Anthemis nobilis L. (roman chamomille): in vitro culture, micropropagation, and the production of essential oil.

peer reviewedaudience: researche

Simulated winter browsing may lead to induced susceptibility of willows to beavers in spring

Browsing may lead to an induced resistance or susceptibility of the plant to the herbivore. We tested the effect of winter browsing by Eurasian beavers (Castor fiber L., 1758) on food quality of holme willows (Salix dasyclados Wimm.) in and after the following growth season. Shrubs were pruned in February, and new shoots from these (cut) shrubs were compared with those of untreated (uncut) ones in May and November. The shoots were analysed for dry matter, nitrogen, acid detergent fibre, and total phenolics. In May, the leaves from the cut treatment had a better food quality (more water, more nitrogen, and less phenolics) than those from the uncut one. There was in part also a systemic response, with lower total phenolics in both the cut and untreated parts of pruned shrubs (uncut–cut) than in the uncut shrubs. In November, we did not find significant differences in biochemistry of bark among cut, uncut, or uncut–cut treatments. These results are in accordance with a cafeteria experiment in the field: in May the beavers preferred shoots from the cut treatment, but in November they showed no preference. The results suggest that willows invest in compensatory growth rather than a defence response early in the regrowing phase.