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Issue Title: \"The Avalonian-Cadomian Belt and related peri-Gondwana Terranes\" Neoproterozoic rocks in the Saxo-Thuringian part of Armorica formed in an active margin setting and were overprinted during Cadomian orogenic processes at the northern margin of Gondwana. The Early Palaeozoic overstep sequence in Saxo-Thuringia was deposited in a Cambro-Ordovician rift setting that reflects the separation of Avalonia and other terranes from the Gondwana mainland. Upper Ordovician and Silurian to Early Carboniferous shelf sediments of Saxo-Thuringia were deposited at the southern passive margin of the Rheic Ocean. SHRIMP U/Pb geochronology on detrital and inherited zircon grains from pre-Variscan basement rocks of the northern part of the Bohemian Massif (Saxo-Thuringia, Germany) demonstrates a distinct West African provenance for sediments and magmatic rocks in this part of peri-Gondwana. Nd-isotope data of Late Neoproterozoic to Early Carboniferous sedimentary rocks show no change in sediment provenance from the Neoproterozoic to the Lower Carboniferous, which implies that Saxo-Thuringia did not leave its West African source before the Variscan Orogeny leading to the Lower Carboniferous configuration of Pangea. Hence, large parts of the pre-Variscan basement of Western and Central Europe often referred to as Armorica or Armorican Terrane Assemblage may have remained with Africa in pre-Pangean time, which makes Armorica a remnant of a \"Greater Africa\" in Gondwanan Europe. The separation of Armorica from the Gondwana mainland and a long drift during the Palaeozoic is not supported by the presented data.[PUBLICATION ABSTRACT]

Issue Title: \"The Avalonian-Cadomian Belt and related peri-Gondwana Terranes\" The Teplá-Barrandian unit (TBU) of the Bohemian Massif was a part of the Avalonian-Cadomian belt at the northern margin of Gondwana during Neoproterozoic and Early Cambrian times. New detrital zircon ages and geochemical compositions of Late Neoproterozoic siliciclastic sediments confirm a deposition of the volcano-sedimentary successions of the TBU in a back-arc basin. A change in the geotectonic regime from convergence to transtension was completed by the time of the Precambrian-Cambrian boundary. The accumulation of around 2,500 m Lower Cambrian continental siliciclastics in a Basin-and-Range-type setting was accompanied by magmatism, which shows within-plate features in a few cases, but is predominantly derived from anatectic melts displaying the inherited island arc signature of their Cadomian source rocks. The geochemistry of clastic sediments suggests a deposition in a rift or strike-slip-related basin, respectively. A marine transgression during Middle Cambrian times indicates markedly thinned crust after the Cadomian orogeny. Upper Cambrian magmatism is represented by 1,500 m of subaerial andesites and rhyolites demonstrating several geochemical characteristics of an intra-plate setting. Zircons from a rhyolite give a U-Pb-SHRIMP age of 499±4 Ma. The Cambrian sedimentary and magmatic succession of the TBU records the beginning of an important rifting event at the northern margin of Gondwana.[PUBLICATION ABSTRACT]

IntroductionChronic kidney disease (CKD) affects 10–15% of the global population. CKD causes systemic inflammation (marked by elevated levels of C-reactive protein, interleukins and tumour necrosis factor-alpha) and CKD-associated cardiomyopathy characterised by increased left ventricular mass, diastolic and systolic dysfunction, profound cardiac fibrosis and atrial and ventricular arrhythmias. The mechanistic links between CKD induced systemic inflammation and cardiac remodelling are unclear, especially in early CKD stages. Therefore, we propose characterizing a CKD mouse model using an adenine-rich diet to compare structural and functional changes in CKD-related cardiomyopathy between early and late stages, and the link to inflammation and other systemic consequences of CKD.Methods8–9-week-old C57BL/6 female and male mice were fed a normal chow or 0.15% adenine rich diet, for up to 7-weeks. Following the diet, blood levels of creatinine and urea were measured to assess kidney dysfunction. Inflammatory markers were sent to be analysed through an o-link panel, and urea and creatinine were analysed through IDEXX. Hearts were isolated for ex vivo cardiac electrophysiological testing and stored for future imaging.ResultsSignificant and progressive increase in urea (5-week, p = 0.0053 and 7-week, p <0.0001) and creatinine (5-week, p = 0.0017 and 7-week, p <0.0001) levels were observed between control and adenine-fed mice, reflecting kidney dysfunction, see figure 1 and figure 2. O-link analysis revealed increases in circulating levels of several inflammatory markers, including interleukin-6, tumor necrosis factor-alpha and C-reactive protein. Although heart weights remained comparable between the two groups, histological evaluation revealed a significant increase in cardiac fibrosis across all chambers (p < 0.0001), rising from 1.35% in control mice, to 3.34% in adenine-fed mice. The right atria identified the largest increase in fibrosis, expanding from 2.16% in control mice to 4.16% in adenine-fed mice.Abstract BS47 Figure 1Indicators of kidney damage in adenine-fed mice. A.) Urea levels from normal chow 7-weeks, and adenine-fed mice at 5 and 7-weeks. 1-way ANOVA test results represented by significant values (p=0.0053 and p<0.0001). B.) Creatinine levels from normal chow 7-weeks, and adenine-fed mice at 5 and 7-weeks. 1-way ANOVA test results represented by significant values (p=0.0017 and p <0.0001)[Figure omitted. See PDF]Abstract BS47 Figure 2O-link inflammatory and cytokine panel, showing percentage increase or decrease between control mice and adenine-fed mice[Figure omitted. See PDF]ConclusionThe adenine-rich diet induced progressive CKD in this mouse model, which is associated with significant systemic inflammation and early cardiac remodelling characterised by increased fibrosis. Ongoing investigations into electrophysiological changes aim to further elucidate the mechanistic link between CKD-induced inflammation and cardiac dysfunction.

The biomechanical properties and responses of tissues underpin a variety important of physiological functions and pathologies. In striated muscle, the actin-binding protein filamin C (FLNC) is a key protein whose variants causative for a wide range of cardiomyopathies and musculoskeletal pathologies. FLNC is a multi-functional protein that interacts with a variety of partners, however, how it is regulated at the molecular level is not well understood. Here we investigate its interaction with HSPB7, a cardiac-specific molecular chaperone whose absence is embryonically lethal. We find that FLNC and HSPB7 interact in cardiac tissue under biomechanical stress, forming a strong hetero-dimer whose structure we solve by X-ray crystallography. Our quantitative analyses show that the hetero-dimer out-competes the FLNC homo-dimer interface, potentially acting to abrogate the ability of the protein to cross-link the actin cytoskeleton, and to enhance its diffusive mobility. We show that phosphorylation of FLNC at threonine 2677, located at the dimer interface and associated with cardiac stress, acts to favour the homo-dimer. Conversely, phosphorylation at tyrosine 2683, also at the dimer interface, has the opposite effect and shifts the equilibrium towards the hetero-dimer. Evolutionary analysis and ancestral sequence reconstruction reveals this interaction and its mechanisms of regulation to date around the time primitive hearts evolved in chordates. Our work therefore shows, structurally, how HSPB7 acts as a specific molecular chaperone that regulates FLNC dimerisation. Filamin C is a key actin-binding protein involved in cardiomyopathies and musculoskeletal disorders. Here, Wang et al reveal that it interacts with the heat shock protein HSPB7 under biomechanical stress, forming a stable hetero-dimer which is regulated by phosphorylation.

The biomechanical properties and responses of tissues underpin a variety of physiological functions and pathologies. In striated muscle, the actin-binding protein filamin C (FLNC) is a key protein whose variants causative for a wide range of cardiomyopathies and musculoskeletal pathologies. Seemingly a multi-functional protein that interacts with a variety of partners, how FLNC is regulated at the molecular level is not well understood. Here we have investigated its interaction with HSPB7, a cardiac-specific molecular chaperone whose absence is embryonically lethal. We found that FLNC and HSPB7 interact in cardiac tissue under biomechanical stress, forming a strong hetero-dimer whose structure we have solved by means of X-ray crystallography. Our quantitative analyses show that the hetero-dimer out-competes the FLNC homo-dimer interface, potentially acting to abrogate the ability of the protein to cross-link the actin cytoskeleton, and to enhance its diffusive mobility. We show that phosphorylation of FLNC at threonine 2677, located at the dimer interface and associated with cardiac stress, acts to favour the homo-dimer. Conversely, phosphorylation at tyrosine 2683, also at the dimer interface, has the opposite effect and shifts the equilibrium towards the hetero-dimer. Evolutionary analysis and ancestral sequence reconstruction reveals this interaction and its mechanisms of regulation to date around the time primitive hearts evolved in chordates. Our work rationalises on the molecular level how FLNC might switch between stabilising functions in the cell, and reveals how HSPB7 acts as a specific molecular chaperone that regulates FLNC.Competing Interest StatementThe authors have declared no competing interest.