On the constitution of sodium at higher densities

Using density functional theory the atomic and electronic structure of sodium are predicted to depart substantially from those expected of simple metals for $r_s 130$ GPa). Newly-predicted phases include those with low structural symmetry, semi-metallic electronic properties (including zero-gap semiconducting limiting behavior), unconventional valence charge density distributions, and even those that raise the possibility of superconductivity, all at currently achievable pressures. Important differences emerge between sodium and lithium at high densities, and these are attributable to corresponding differences in their respective cores.Comment: 13 pages; 3 figure

Fullerene‐like structures of Cretaceous crinoids reveal topologically limited skeletal possibilities

There are few cases where numbers or types of possible phenotypes are known, although vast state spaces have been postulated. Rarely applied in this context, graph theory and topology enable enumeration of possible phenotypes and evolutionary transitions. Here, we generate polyhedral calyx graphs for the Late Cretaceous, stemless crinoids Marsupites testudinarius and Uintacrinus socialis (Uintacrinoidea Zittel) revealing structural similarities to carbon fullerene and fulleroid molecules (respectively). The U. socialis calyx incorporates numerous plates (e.g. graph vertices |V| ≥ 197), which are small, light, low‐density and have four to eight sides. Therefore, the corresponding number of possible plate arrangements (number of polyhedral graphs) is large (≫1 × 1014). Graph vertices representing plates with sides >6 introduce negative Gaussian curvature (surface saddle points) and topological instability, increasing buckling risk. However, observed numbers of vertices for Uintacrinus do not allow more stable pentaradial configurations. In contrast, the Marsupites calyx dual graph has 17 faces that are pentagonal or hexagonal. Therefore, it is structurally identical to a carbon fullerene, specifically C30‐D5h. Corresponding graph restrictions result in constraint to only three structural options (fullerene structures C30‐C2v 1, C30‐C2v 2 and C30‐D5h). Further restriction to pentaradial symmetry allows only one possibility: the Marsupites phenotype. This robust, stable topology is consistent with adaptation to predation pressures of the Mesozoic marine revolution. Consequently, the most plausible evolutionary pathway between unitacrinoid phenotypes was a mixed heterochronic trade‐off to fewer, larger calyx plates. Therefore, topological limitations radically constrained uintacrinoid skeletal possibilities but thereby aided evolution of a novel adaptive phenotype

The Sail-Backed Reptile Ctenosauriscus from the Latest Early Triassic of Germany and the Timing and Biogeography of the Early Archosaur Radiation

Background Archosaurs (birds, crocodilians and their extinct relatives including dinosaurs) dominated Mesozoic continental ecosystems from the Late Triassic onwards, and still form a major component of modern ecosystems (>10,000 species). The earliest diverse archosaur faunal assemblages are known from the Middle Triassic (c. 244 Ma), implying that the archosaur radiation began in the Early Triassic (252.3–247.2 Ma). Understanding of this radiation is currently limited by the poor early fossil record of the group in terms of skeletal remains. Methodology/Principal Findings We redescribe the anatomy and stratigraphic position of the type specimen of Ctenosauriscus koeneni (Huene), a sail-backed reptile from the Early Triassic (late Olenekian) Solling Formation of northern Germany that potentially represents the oldest known archosaur. We critically discuss previous biomechanical work on the ‘sail’ of Ctenosauriscus, which is formed by a series of elongated neural spines. In addition, we describe Ctenosauriscus-like postcranial material from the earliest Middle Triassic (early Anisian) Röt Formation of Waldhaus, southwestern Germany. Finally, we review the spatial and temporal distribution of the earliest archosaur fossils and their implications for understanding the dynamics of the archosaur radiation. Conclusions/Significance Comprehensive numerical phylogenetic analyses demonstrate that both Ctenosauriscus and the Waldhaus taxon are members of a monophyletic grouping of poposauroid archosaurs, Ctenosauriscidae, characterised by greatly elongated neural spines in the posterior cervical to anterior caudal vertebrae. The earliest archosaurs, including Ctenosauriscus, appear in the body fossil record just prior to the Olenekian/Anisian boundary (c. 248 Ma), less than 5 million years after the Permian–Triassic mass extinction. These earliest archosaur assemblages are dominated by ctenosauriscids, which were broadly distributed across northern Pangea and which appear to have been the first global radiation of archosaurs

A critical appraisal of appendage disparity and homology in fishes

Fishes are both extremely diverse and morphologically disparate. Part of this disparity can be observed in the numerous possible fin configurations that may differ in terms of the number of fins as well as fin shapes, sizes and relative positions on the body. Here, we thoroughly review the major patterns of disparity in fin configurations for each major group of fishes and discuss how median and paired fin homologies have been interpreted over time. When taking into account the entire span of fish diversity, including both extant and fossil taxa, the disparity in fin morphologies greatly complicates inferring homologies for individual fins. Given the phylogenetic scope of this review, structural and topological criteria appear to be the most useful indicators of fin identity. We further suggest that it may be advantageous to consider some of these fin homologies as nested within the larger framework of homologous fin‐forming morphogenetic fields. We also discuss scenarios of appendage evolution and suggest that modularity may have played a key role in appendage disparification. Fin modules re‐expressed within the boundaries of fin‐forming fields could explain how some fins may have evolved numerous times independently in separate lineages (e.g., adipose fin), or how new fins may have evolved over time (e.g., anterior and posterior dorsal fins, pectoral and pelvic fins). We favour an evolutionary scenario whereby median appendages appeared from a unique field of competence first positioned throughout the dorsal and ventral midlines, which was then redeployed laterally leading to paired appendages.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151971/1/faf12402_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151971/2/faf12402.pd

Relevance of genetic testing in the gene-targeted trial era: the Rostock Parkinson\u27s disease study

\ua9 The Author(s) 2024. Estimates of the spectrum and frequency of pathogenic variants in Parkinson’s disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinson’s disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (∼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 7 10−34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 7 10−35). Female patients were 22% more likely to have a positive PDGT (P = 3 7 10−4), and for individuals with FH+ this likelihood was 55% higher (P = 1 7 10−14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that ∼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD

Upper Toarcian (Lower Jurassic) marine gastropods from the Cleveland Basin, England: systematics, palaeobiogeography and contribution to biotic recovery from the early Toarcian extinction event

Here we describe a new upper Toarcian (Lower Jurassic) marine gastropod fauna from rocks of the Cleveland Basin exposed on the North Yorkshire coast of England. The fossil assemblage consists of 16 species, of which three are new: Katosira ? bicarinata sp. nov., Turritelloidea stepheni sp. nov. and Striactaenonina elegans sp. nov. Four species are described in open nomenclature as Tricarilda ? sp., Jurilda sp., Cylindrobullina sp. and Cossmannina sp. The other species have previously been described: Coelodiscus minutus (Schübler in Zieten), Procerithium quadrilineatum (Römer), Pseudokatosira undulata (Benz in von Zieten), Palaeorissoina aff. acuminata (Gründel), Pietteia unicarinata (Hudleston), Globularia cf. canina (Hudleston), Striactaeonina cf. richterorum Schulbert & Nützel, Striactaenonina aff. tenuistriata (Hudleston) and Sulcoactaeon sedgvici (Phillips). Most of these species are the earliest records of their respective genera and show palaeobiogeographical connections with contemporary gastropod associations from other regions of Europe and South America. The taxonomic composition of the upper Toarcian Cleveland Basin gastropod assemblage differs substantially from the faunas of the upper Pliensbachian and lower Toarcian Tenuicostatum Zone, showing the strong effect of the early Toarcian mass extinction event on the marine gastropod communities in the basin. Only a few gastropod species are shared between the late Toarcian faunas and the much more diverse Aalenian gastropod faunas in the Cleveland Basin, suggesting that there was a facies control on gastropod occurrences at that time. This is also a potential explanation for the taxonomic differences between the late Toarcian gastropod faunas in the Cleveland Basin and those in France, and northern and southern Germany

The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients

The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the “REGISTRY” cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation