In Silico Derivation of HLA-Specific Alloreactivity Potential from Whole Exome Sequencing of Stem Cell Transplant Donors and Recipients: Understanding the Quantitative Immuno-biology of Allogeneic Transplantation

Donor T cell mediated graft vs. host effects may result from the aggregate alloreactivity to minor histocompatibility antigens (mHA) presented by the HLA in each donor-recipient pair (DRP) undergoing stem cell transplantation (SCT). Whole exome sequencing has demonstrated extensive nucleotide sequence variation in HLA-matched DRP. Non-synonymous single nucleotide polymorphisms (nsSNPs) in the GVH direction (polymorphisms present in recipient and absent in donor) were identified in 4 HLA-matched related and 5 unrelated DRP. The nucleotide sequence flanking each SNP was obtained utilizing the ANNOVAR software package. All possible nonameric-peptides encoded by the non-synonymous SNP were then interrogated in-silico for their likelihood to be presented by the HLA class I molecules in individual DRP, using the Immune-Epitope Database (IEDB) SMM algorithm. The IEDB-SMM algorithm predicted a median 18,396 peptides/DRP which bound HLA with an IC50 of <500nM, and 2254 peptides/DRP with an IC50 of <50nM. Unrelated donors generally had higher numbers of peptides presented by the HLA. A similarly large library of presented peptides was identified when the data was interrogated using the Net MHCPan algorithm. These peptides were uniformly distributed in the various organ systems. The bioinformatic algorithm presented here demonstrates that there may be a high level of minor histocompatibility antigen variation in HLA-matched individuals, constituting an HLA-specific alloreactivity potential. These data provide a possible explanation for how relatively minor adjustments in GVHD prophylaxis yield relatively similar outcomes in HLA matched and mismatched SCT recipients.Comment: Abstract: 235, Words: 6422, Figures: 7, Tables: 3, Supplementary figures: 2, Supplementary tables:

High-Transconductance Graphene Solution-Gated Field Effect Transistors

In this work, we report on the electronic properties of solution-gated field effect transistors (SGFETs) fabricated using large-area graphene. Devices prepared both with epitaxially grown graphene on SiC as well as with chemical vapor deposition grown graphene on Cu exhibit high transconductances, which are a consequence of the high mobility of charge carriers in graphene and the large capacitance at the graphene/water interface. The performance of graphene SGFETs, in terms of gate sensitivity, is compared to other SGFET technologies and found to be clearly superior, confirming the potential of graphene SGFETs for sensing applications in electrolytic environments.Comment: The following article has been submitted to Applied Physics Letters. After it is published, it will be found at apl.aip.or

Sedimentary evidence of the Late Holocene tsunami in the Shetland Islands (UK) at Loch Flugarth, northern Mainland

Tsunami deposits around the North Sea basin are needed to assess the long-term hazard of tsunamis. Here, we present sedimentary evidence of the youngest tsunami on the Shetland Islands from Loch Flugarth, a coastal lake on northern Mainland. Three gravity cores show organic-rich background sedimentation with many sub-centimetre-scale sand layers, reflecting recurring storm overwash and a sediment source limited to the active beach and uppermost subtidal zone. A basal 13-cm-thick sand layer, dated to 426–787 cal. a CE based on 14C, 137Cs and Bayesian age–depth modelling, was found in all cores. High-resolution grain-size analysis identified four normally graded or massive sublayers with inversely graded traction carpets at the base of two sublayers. A thin organic-rich ‘mud’ drape and a ‘mud’ cap cover the two uppermost sublayers, which also contain small rip-up clasts. Grain-size distributions show a difference between the basal sand layer and the coarser and better sorted storm layers above. Multivariate statistical analysis of X-ray fluorescence core scanning data also distinguishes both sand units: Zr, Fe and Ti dominate the thick basal sand, while the thin storm layers are high in K and Si. Enriched Zr and Ti in the basal sand layer, in combination with increased magnetic susceptibility, may be related to higher heavy mineral content reflecting an additional marine sediment source below the storm-wave base that is activated by a tsunami. Based on reinterpretation of chronological data from two different published sites and the chronostratigraphy of the present study, the tsunami seems to date to c. 1400 cal. a BP. Although the source of the tsunami remains unclear, the lack of evidence for this event outside of the Shetland Islands suggests that it had a local source and was smaller than the older Storegga tsunami (8.15 cal. ka BP), which affected most of the North Sea basin.</p

A 1500‐year record of North Atlantic storm flooding from lacustrine sediments, Shetland Islands (UK)

Severe storm flooding poses a major hazard to the coasts of north‐western Europe. However, the long‐term recurrence patterns of extreme coastal flooding and their governing factors are poorly understood. Therefore, high‐resolution sedimentary records of past North Atlantic storm flooding are required. This multi‐proxy study reconstructs storm‐induced overwash processes from coastal lake sediments on the Shetland Islands using grain‐size and geochemical data, and the re‐analysis of historical data. The chronostratigraphy is based on Bayesian age–depth modelling using accelerator mass spectrometry 14 C and 137 Cs data. A high XRF‐based Si/Ti ratio and the unimodal grain‐size distribution link the sand layers to the beach and thus storm‐induced overwash events. Periods with more frequent storm flooding occurred 980–1050, 1150–1300, 1450–1550, 1820–1900 and 1950–2000 ce, which is largely consistent with a positive North Atlantic Oscillation mode. The Little Ice Age (1400–1850 ce ) shows a gap of major sand layers suggesting a southward shift of storm tracks and a seasonal variance with more storm floods in spring and autumn. Warmer phases shifted winter storm tracks towards the north‐east Atlantic, indicating a possible trend for future storm‐track changes and increased storm flooding in the northern North Sea region

Elevated serum levels of methylglyoxal are associated with impaired liver function in patients with liver cirrhosis

Methylglyoxal (MGO) is a highly reactive dicarbonyl species that forms advanced glycation end products (AGEs). The binding of these AGEs to their receptor (RAGE) causes and sustains severe inflammation. Systemic inflammation is postulated to be a major driver in the progression of liver cirrhosis. However, the role of circulating MGO levels in liver cirrhosis remains unknown. In this study, we investigated the serum levels of two dicarbonyl species, MGO and glyoxal (GO) using tandem mass spectrometry (HPLC–MS/MS) and evaluated their association with disease severity. A total of 51 inpatients and outpatients with liver cirrhosis of mixed etiology and different disease stages were included. Elevated MGO levels were seen in an advanced stage of liver cirrhosis (p < 0.001). High MGO levels remained independently associated with impaired liver function, as assessed by the model for end-stage liver disease (MELD) (β = 0.448, p = 0.002) and acute decompensation (AD) (β = 0.345, p = 0.005) scores. Furthermore, MGO was positively correlated with markers of systemic inflammation (IL-6, p = 0.004) and the development of ascites (p = 0.013). In contrast, no changes were seen in GO serum levels. Circulating levels of MGO are elevated in advanced stages of liver cirrhosis and are associated with impaired liver function and liver-related parameters

Biomarkers of rapid chronic kidney disease progression in type 2 diabetes.

Here we evaluated the performance of a large set of serum biomarkers for the prediction of rapid progression of chronic kidney disease (CKD) in patients with type 2 diabetes. We used a case-control design nested within a prospective cohort of patients with baseline eGFR 30-60 ml/min per 1.73 m(2). Within a 3.5-year period of Go-DARTS study patients, 154 had over a 40% eGFR decline and 153 controls maintained over 95% of baseline eGFR. A total of 207 serum biomarkers were measured and logistic regression was used with forward selection to choose a subset that were maximized on top of clinical variables including age, gender, hemoglobin A1c, eGFR, and albuminuria. Nested cross-validation determined the best number of biomarkers to retain and evaluate for predictive performance. Ultimately, 30 biomarkers showed significant associations with rapid progression and adjusted for clinical characteristics. A panel of 14 biomarkers increased the area under the ROC curve from 0.706 (clinical data alone) to 0.868. Biomarkers selected included fibroblast growth factor-21, the symmetric to asymmetric dimethylarginine ratio, β2-microglobulin, C16-acylcarnitine, and kidney injury molecule-1. Use of more extensive clinical data including prebaseline eGFR slope improved prediction but to a lesser extent than biomarkers (area under the ROC curve of 0.793). Thus we identified several novel associations of biomarkers with CKD progression and the utility of a small panel of biomarkers to improve prediction.We acknowledge all the SUMMIT partners (http://www.imi-summit.eu/) for their assistance with this project. This work was funded by the Innovative Medicine Initiative under grant agreement no. IMI/115006 (the SUMMIT consortium) and the Go-DARTS cohort was funded by the Chief Scientists Office Scotland.This is the accepted manuscript of a paper published in Kidney International (Looker et al., Kidney International, 2015 doi: 10.1038/ki.2015.199). The final version is available at http://dx.doi.org/10.1038/ki.2015.19