Plasma proteomic profiles of UK Biobank participants with multiple sclerosis.

OBJECTIVE: We aimed to describe plasma protein biomarkers of multiple sclerosis risk and to explore protein biomarkers of disease severity using radiological outcome measures. METHODS: Multiple sclerosis cases and controls were identified in UK Biobank, a longitudinal cohort study of ~500,000 British adults. Plasma proteins were assayed in ~50,000 UK Biobank participants using the Olink proximity extension assay. We performed case-control association testing to examine the association between 2911 proteins and multiple sclerosis, using linear models adjusted for confounding covariates. Associations with radiological lesion burden and brain volume were determined in a subset of the cohort with available magnetic resonance imaging, using normalized T2-hyperintensity volume or whole brain volume as the outcome measure. RESULTS: In total, 407 prevalent multiple sclerosis cases and 39,979 healthy controls were included. We discovered 72 proteins associated with multiple sclerosis at a Bonferroni-adjusted p value of 0.05, including established markers such as neurofilament light chain and glial fibrillary acidic protein. We observed a decrease in plasma Granzyme A, a marker of T cell and NK cell degranulation, which was specific to multiple sclerosis. Higher levels of plasma proteins involved in coagulation were associated with lower T2 lesion burden and preserved brain volume. INTERPRETATION: We report the largest plasma proteomic screen of multiple sclerosis, replicating important known associations and suggesting novel markers, such as the reduction in granzyme A. While these findings require external validation, they demonstrate the power of biobank-scale datasets for discovering new biomarkers for multiple sclerosis

Smooth-muscle myosin mutations in hereditary non-polyposis colorectal cancer syndrome

We examined adenomas and cancers from hereditary non-polyposis colorectal cancer (HNPCC) syndrome patients for the presence of frameshift mutations in the smooth-muscle myosin gene, MYH11. Our results show that mutations in MYH11 occur more frequently in cancers than adenomas (P=0.008) and are dependent on microsatellite instability (MSI+)

Label-free segmentation of co-cultured cells on a nanotopographical gradient

The function and fate of cells is influenced by many different factors, one of which is surface topography of the support culture substrate. Systematic studies of nanotopography and cell response have typically been limited to single cell types and a small set of topographical variations. Here, we show a radical expansion of experimental throughput using automated detection, measurement, and classification of co-cultured cells on a nanopillar array where feature height changes continuously from planar to 250 nm over 9 mm. Individual cells are identified and characterized by more than 200 descriptors, which are used to construct a set of rules for label-free segmentation into individual cell types. Using this approach we can achieve label-free segmentation with 84% confidence across large image data sets and suggest optimized surface parameters for nanostructuring of implant devices such as vascular stents

An NF-κB and Slug Regulatory Loop Active in Early Vertebrate Mesoderm

BACKGROUND: In both Drosophila and the mouse, the zinc finger transcription factor Snail is required for mesoderm formation; its vertebrate paralog Slug (Snai2) appears to be required for neural crest formation in the chick and the clawed frog Xenopus laevis. Both Slug and Snail act to induce epithelial to mesenchymal transition (EMT) and to suppress apoptosis. METHODOLOGY & PRINCIPLE FINDINGS: Morpholino-based loss of function studies indicate that Slug is required for the normal expression of both mesodermal and neural crest markers in X. laevis. Both phenotypes are rescued by injection of RNA encoding the anti-apoptotic protein Bcl-xL; Bcl-xL's effects are dependent upon IκB kinase-mediated activation of the bipartite transcription factor NF-κB. NF-κB, in turn, directly up-regulates levels of Slug and Snail RNAs. Slug indirectly up-regulates levels of RNAs encoding the NF-κB subunit proteins RelA, Rel2, and Rel3, and directly down-regulates levels of the pro-apopotic Caspase-9 RNA. CONCLUSIONS/SIGNIFICANCE: These studies reveal a Slug/Snail–NF-κB regulatory circuit, analogous to that present in the early Drosophila embryo, active during mesodermal formation in Xenopus. This is a regulatory interaction of significance both in development and in the course of inflammatory and metastatic disease

Vitamin D genetic risk scores in multiple sclerosis

BACKGROUND: Low serum 25(OH)D(3) (vD) is an environmental risk factor for multiple sclerosis (MS). Lower vD levels during early disease may be associated with long-term disability. Determinants of serum vD levels in healthy individuals include supplementation behaviour and genetic factors. These determinants have been less well studied in people with MS (pwMS). METHODS: We developed a vD-weighted genetic risk score (GRS) and validated this in 373,357 UK Biobank participants without MS. We measured serum 25(OH)D(3) and genotyped six vD-associated SNPs (rs12785878, rs10741657, rs17216707, rs10745742, rs8018720, rs2282679) in a cohort of pwMS (n = 315) with age and geographically matched controls (n = 232). We then assessed predictors of serum vD concentration in this cohort. RESULTS: The GRS was strongly associated with vD status in the Biobank cohort (p < 2 × 10(–16)). vD supplementation, having MS, lower BMI, increased age and supplementation dose were associated with higher vD levels (false discovery rate, FDR < 5%). In multivariable models adjusting for supplementation, BMI, age, sex, and MS status, the GRS was strongly associated with vD level (p = 0.004), but not in those who supplemented (p = 0.47). CONCLUSIONS: Our findings suggest that vD supplementation is the major determinant of vD level in pwMS, with genetic determinants playing a far smaller role