Osteochondritis dissecans is a disorder in which fragments of articular cartilage and subchondral bone dislodge from the joint surface. We analyzed a five-generation family in which affected members ...had autosomal-dominant familial osteochondritis dissecans. A genome-wide linkage analysis identified aggrecan (ACAN) as a prime candidate gene for the disorder. Sequence analysis of ACAN revealed heterozygosity for a missense mutation (c.6907G > A) in affected individuals, resulting in a p.V2303M amino acid substitution in the aggrecan G3 domain C-type lectin, which mediates interactions with other proteins in the cartilage extracellular matrix. Binding studies with recombinant mutated and wild-type G3 proteins showed loss of fibulin-1, fibulin-2, and tenascin-R interactions for the V2303M protein. Mass spectrometric analyses of aggrecan purified from patient cartilage verified that V2303M aggrecan is produced and present in the tissue. Our results provide a molecular mechanism for the etiology of familial osteochondritis dissecans and show the importance of the aggrecan C-type lectin interactions for cartilage function in vivo.
Technologies for profiling samples using different omics platforms have been at the forefront since the human genome project. Large-scale multi-omics data hold the promise of deciphering different ...regulatory layers. Yet, while there is a myriad of bioinformatics tools, each multi-omics analysis appears to start from scratch with an arbitrary decision over which tools to use and how to combine them. Therefore, it is an unmet need to conceptualize how to integrate such data and implement and validate pipelines in different cases. We have designed a conceptual framework (STATegra), aiming it to be as generic as possible for multi-omics analysis, combining available multi-omic anlaysis tools (machine learning component analysis, non-parametric data combination, and a multi-omics exploratory analysis) in a step-wise manner. While in several studies, we have previously combined those integrative tools, here, we provide a systematic description of the STATegra framework and its validation using two The Cancer Genome Atlas (TCGA) case studies. For both, the Glioblastoma and the Skin Cutaneous Melanoma (SKCM) cases, we demonstrate an enhanced capacity of the framework (and beyond the individual tools) to identify features and pathways compared to single-omics analysis. Such an integrative multi-omics analysis framework for identifying features and components facilitates the discovery of new biology. Finally, we provide several options for applying the STATegra framework when parametric assumptions are fulfilled and for the case when not all the samples are profiled for all omics. The STATegra framework is built using several tools, which are being integrated step-by-step as OpenSource in the STATeg
a Bioconductor package.
Dysregulation of signaling pathways in multiple sclerosis (MS) can be analyzed by phosphoproteomics in peripheral blood mononuclear cells (PBMCs). We performed in vitro kinetic assays on PBMCs in 195 ...MS patients and 60 matched controls and quantified the phosphorylation of 17 kinases using xMAP assays. Phosphoprotein levels were tested for association with genetic susceptibility by typing 112 single-nucleotide polymorphisms (SNPs) associated with MS susceptibility. We found increased phosphorylation of MP2K1 in MS patients relative to the controls. Moreover, we identified one SNP located in the PHDGH gene and another on IRF8 gene that were associatedwith MP2K1 phosphorylation levels, providing a first clue on how this MS risk gene may act. The analyses in patients treated with disease-modifying drugs identified the phosphorylation of each receptor’s downstream kinases. Finally, using flow cytometry, we detected in MS patients increased STAT1, STAT3, TF65, and HSPB1 phosphorylation in CD19⁺ cells. These findings indicate the activation of cell survival and proliferation (MAPK), and proinflammatory (STAT) pathways in the immune cells of MS patients, primarily in B cells. The changes in the activation of these kinases suggest that these pathways may represent therapeutic targets for modulation by kinase inhibitors.
The response of a matrix of 25 lead tungstate (PWO) scintillator detectors, operated at a25 degC, to photons in the range 13 MeVa64 MeV has been measured at the tagged-photon facility at MAX-lab, ...Lund. The tapered PWO crystals, each with a length of 200 mm and a cross-section of 24.4A24.4 mm2 in the front end, read out by 19 mm photomultiplier tubes, were arranged in a 5A5 matrix. The response was measured for photons directed towards the centre of the central crystal as well as for photons directed towards the corner of the central crystal, where four crystals meet. The obtained energy resolution surpasses what has been published so far and is close to the limit given by Poisson statistics and escaped energy. For photons directed towards the centre(corner) of the central crystal the relative energy resolution, defined as (FWHM/2.35) / E gamma , decreases from 7.3%(11.0%) at E gamma = 13 MeV to 3.3%(3.6%) at E gamma = 64 MeV . The reconstructed point of impact of a photon in this energy range is determined with an uncertainty (one standard deviation) of 7.3A-0.1 mm.
Multiple Sclerosis (MS) is an autoimmune disease driving inflammatory and degenerative processes that damage the central nervous system (CNS). However, it is not well understood how these events ...interact and evolve to evoke such a highly dynamic and heterogeneous disease. We established a hypothesis whereby the variability in the course of MS is driven by the very same pathogenic mechanisms responsible for the disease, the autoimmune attack on the CNS that leads to chronic inflammation, neuroaxonal degeneration and remyelination. We propose that each of these processes acts more or less severely and at different times in each of the clinical subgroups. To test this hypothesis, we developed a mathematical model that was constrained by experimental data (the expanded disability status scale EDSS time series) obtained from a retrospective longitudinal cohort of 66 MS patients with a long-term follow-up (up to 20 years). Moreover, we validated this model in a second prospective cohort of 120 MS patients with a three-year follow-up, for which EDSS data and brain volume time series were available. The clinical heterogeneity in the datasets was reduced by grouping the EDSS time series using an unsupervised clustering analysis. We found that by adjusting certain parameters, albeit within their biological range, the mathematical model reproduced the different disease courses, supporting the dynamic CNS damage hypothesis to explain MS heterogeneity. Our analysis suggests that the irreversible axon degeneration produced in the early stages of progressive MS is mainly due to the higher rate of myelinated axon degeneration, coupled to the lower capacity for remyelination. However, and in agreement with recent pathological studies, degeneration of chronically demyelinated axons is not a key feature that distinguishes this phenotype. Moreover, the model reveals that lower rates of axon degeneration and more rapid remyelination make relapsing MS more resilient than the progressive subtype. Therefore, our results support the hypothesis of a common pathogenesis for the different MS subtypes, even in the presence of genetic and environmental heterogeneity. Hence, MS can be considered as a single disease in which specific dynamics can provoke a variety of clinical outcomes in different patient groups. These results have important implications for the design of therapeutic interventions for MS at different stages of the disease.
Equilibria between plagioclase and ferrobasaltic melt in low-pressure, dry melting experiments can be demonstrated near the liquidus. Further analyses of melting experiments using optimized beam ...conditions reveals that previous data for understanding the Skaergaard intrusion potentially suffered from the analytical inclusion of non-equilibrated components in the average plagioclase compositions. New reversal experiments demonstrate convergence between plagioclase rim compositions in melting and crystallization products for a ferrobasaltic melt and thus support equilibrium relations. The new data set provides tighter bounds on experimental plagioclase composition and documents composition-dependent partitioning of Na and Ca between plagioclase and melt. Application of the results to modeling the Skaergaard requires only minor adjustments to the previously proposed liquidus temperatures and liquid line of descent.
Red abalones (Haliotis rufescens), red sea urchins (Strongylocentrotus franciscanus), and purple sea urchins (S. purpuratus) share similar food and habitat requirements in northern California. Red ...abalones and red sea urchins also support important fisheries. Here we explore spatial interactions and apparent competitive effects among these species at an area where fishing has large impacts on both taxa, and at unfished reserve sites in which invertebrate density and food availability differ. There was an inverse correlation between adult red abalone and red sea urchin abundance at the scale of our transects when density of either or both species was high. In the poorest habitat for macroalgae, red abalones seldom occurred on the same transects with red urchins. The results suggest that differences in density, depth, and food availability play an important role in the observed spatial patterns of red abalones and red sea urchins. Purple sea urchins were not correlated to either of the other two species' distributions. An intense fishery for red sea urchins appears to have had a positive effect on kelp availability, and abalone growth and abundance. Aerial photographs during the period of intense urchin fishing (from 1982 to 1989), showed a dramatic increase in the surface canopy. Similarly, during this period, size frequency distributions of fished red abalones show an increase in the number of individuals in larger size classes. Modal progression in abalone size frequency distributions suggests a faster growth rate during this period when compared with a growth study, at the same location, conducted during the pre-urchin fishery years. Ultimately, red sea urchin removal apparently led to an increase in red abalone abundance even at a site that was heavily fished by recreational abalone fishers. Meanwhile, at a nearby reserve site where kelp populations are lower, red abalones have declined in abundance as red sea urchins increased. Our results suggest the need for multi-species ecosystem-based approaches to management of these valuable resources.
Abstract While basaltic volcanism is dominant during rifting and continental breakup, felsic magmatism may be a significant component of some rift margins. During International Ocean Discovery ...Program (IODP) Expedition 396 on the continental margin of Norway, a graphite‐garnet‐cordierite bearing dacitic unit (the Mimir dacite) was recovered in two holes within early Eocene sediments on Mimir High (Site U1570), a marginal high on the Vøring Transform Margin. Here, we present a comprehensive textural, petrological, and geochemical study of the Mimir dacite in order to assess its origin and discuss the geodynamic implications. The major mineral phases (garnet, cordierite, quartz, plagioclase, alkali feldspar) are hosted in a fresh rhyolitic, vesicular, glassy matrix that is locally mingled with sediments. The major element chemistry of garnet and cordierite, the presence of zircon inclusions with inherited cores, and thermobarometric calculations all support an upper crustal metapelitic origin. While most magma‐rich margin models favor crustal anatexis in the lower crust, thermobarometric calculations performed here show that the Mimir dacite was produced at upper‐crustal depths (<5 kbar, 18 km depth) and high temperature (750–800°C) with up to 3 wt% water content. In situ U‐Pb analyses on zircon inclusions give a magmatic crystallization age of 54.6 ± 1.1 Ma, consistent with emplacement that post‐dates the Paleocene‐Eocene Thermal Maximum. Our results suggest that the opening of the Northeast Atlantic was associated with a phase of low‐pressure, high‐temperature crustal anatexis preceding the main phase of magmatism.
Plain Language Summary Fifty‐six million years ago, the continents were beginning the final phase of their journey to their modern‐day locations. This included the rifting and formation of the Northeast Atlantic Ocean, known in particular for producing considerable magmatism during continental break‐up. In summer 2021, Expedition 396 of the International Ocean Discovery Program drilled the oceanic floor off the coast of present‐day Norway to collect volcanic and sedimentary rocks deposited at this time. Their main goal was to investigate the cause of the excess magmatism and its potential implications for the global climate. While sampling sediments on the expedition, an unexpected volcanic unit, a glassy garnet‐cordierite dacite, was recovered. To determine its origin, we combined multiple methods (petrography, stratigraphy, thermodynamic calculations, petrochronology, in situ compositional analyses) and showed that the unit is a product of melting of in the continental crust at shallow depth during the rifting process and likely later emplaced in shallow water. Our results demonstrate that the rifting process in the Northeast Atlantic included a long and intense period of continental crustal thinning. This research provides evidence needed to reconstruct the evolution of the Northeast Atlantic Ocean.
Key Points A dacitic unit was recovered in early Eocene sediments on the Vøring margin during International Ocean Discovery Program Expedition 396 The Mimir dacite was formed by upper crustal anatexis at 54.6 ± 1.1 Ma, shortly after the Paleocene‐Eocene Thermal Maximum The dacite is evidence for a break‐up phase associated with significant continental lithospheric extension
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